Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome

ABSTRACT

The present invention relates to methods for treating and/or preventing podocytes related disorders and/or nephrotic syndrome comprising the administration of an effective amount of a certain DPP-4 inhibitor, as well as to the use of a certain DPP-4 inhibitor for treating and/or preventing a metabolic disease in a patient with or at risk of podocytes related disorders and/or nephrotic syndrome.

FIELD OF THE INVENTION

The present invention relates to a certain DPP-4 inhibitor (preferablylinagliptin, optionally in combination with one or more other activeagents) for use in treating, preventing and/or reducing the risk orlikelihood of podocyte related disorders, disturbance of podocytefunction, podocyte loss or injury, podocytopathy, glomerulopathy,nephrotic syndrome, minimal change disease (MCD, e.g. minimal changenephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS),and/or diseases related or associated therewith, to pharmaceuticalcompositions and combinations comprising such active components, and tocertain therapeutic uses thereof.

BACKGROUND OF THE INVENTION

Disturbance of podocyte function as well as podocyte loss or injury area hallmark of a variety of primary or secondary proteinuric glomerulardiseases such as minimal change disease (such as e.g. minimal changenephropathy, or steroid hormone refractory minimal change nephropathy),focal segmental glomerulosclerosis (FSGS) and membraneous nephropathy(such as e.g. membranous glomerulonephritis). These diseases may presentas a nephrotic syndrome, which is characterized by proteinuria(typically >3 g/day, or >3.5 g per 1.73 m² per 24 hours), edema (whichmay be associated with weight gain), hypoalbuminemia (typically albuminlevel ≤2.5 g/dL), hyperlipidemia (e.g. hypercholesterolemia,hypertriglyceridemia, or both in combined hyperlipidemia, particularlyhypercholesterolemia, mainly elevated LDL, usually with concomitantlyelevated VLDL) and optionally (sometimes) hypertension. Lipiduria mayalso occur, but is not essential for the diagnosis of nephroticsyndrome. Hyponatremia may also occur with a low fractional sodiumexcretion.

Injury to the podocyte results in proteinuria and often leads toprogressive kidney disease. As podocytes have limited ability to repairand/or regenerate, the extent of podocyte injury is a major prognosticdeterminant in diabetic nephropathy and other common causes of end-stagerenal disease. Therapies aimed at preventing or limiting podocyte injuryand/or at promoting podocyte repair or regeneration therefore have majorpotential clinical and economic benefits. Many currenttherapies—including glucocorticosteroids (e.g. prednisone,prednisolone), cyclophosphamide, cyclosporine, rituximab and calcineurinantagonists—have some effects on podocytes. However there are conditionsof nephrotic syndrome which are or become resistant or refractory(relapsing) to conventional therapy, e.g. to steroid treatment. Further,the nonspecific natures of these conventional agents can lead toundesirable systemic adverse effects.

If protein excretion can not be controlled by adequate therapy, thesediseases often progress to end-stage renal disease. This is particularlytrue for steroid hormone refractory minimal change nephropathy and focalsegmental glomerulosclerosis (FSGS). The “normal” (steroid sensitive)minimal change nephropathy usually responds well to treatment withsteroids. With steroid hormone refractory minimal change nephropathy andfocal segmental glomerulosclerosis (FSGS), however, there remainclinical circumstances where no effective treatment is available today.

Nephrotic syndrome has many causes and may either be the result of adisease limited to the kidney, called primary nephrotic syndrome, or acondition that affects the kidney and other parts of the body, calledsecondary nephrotic syndrome.

Primary Nephrotic Syndrome:

Primary causes of nephrotic syndrome are usually described by thehistology, i.e. minimal change disease (MCD) such as minimal changenephropathy which is the most common cause of nephrotic syndrome inchildren, focal segemental glomerulosclerosis (FSGS) and membraneousnephropathy (MN) such as membraneous glomerulonephritis which is themost common cause of nephrotic syndrome in adults.

They are considered to be “diagnoses of exclusion”, i.e. they arediagnosed only after secondary causes have been excluded.

Secondary Nephrotic Syndrome:

Secondary causes of nephrotic syndrome have the same histologic patternsas the primary causes, though may exhibit some differences suggesting asecondary cause, such as inclusion bodies. They are usually described bythe underlying cause.

Secondary causes by histologic pattern:

Membranous nephropathy (MN):

-   -   Hepatitis B & Hepatitis C    -   Sjögren's syndrome    -   Systemic lupus erythematosus (SLE)    -   Diabetes mellitus    -   Sarcoidosis    -   Drugs (such as corticosteroids, gold, intravenous heroin)    -   Malignancy (cancer)    -   Bacterial infections, e.g. leprosy & syphilis    -   Protozoal infections, e.g. malaria        Focal segmental glomerulosclerosis (FSGS):    -   Hypertensive nephrosclerosis    -   HIV    -   Obesity    -   Kidney loss        Minimal change disease (MCD):    -   Drugs, especially NSAIDs in the elderly    -   Malignancy, especially Hodgkin's lymphoma    -   Leukemia

Accordingly, nephrotic syndrome within the meaning of this inventionincludes, is caused by or is associated with minimal change disease(MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS).

SUMMARY OF THE INVENTION

The present invention relates to a certain DPP-4 inhibitor (preferablylinagliptin, optionally in combination with one or more other activeagents) for use in treating, preventing and/or reducing the risk orlikelihood of podocyte related disorders, disturbance of podocytefunction, podocyte loss or injury, podocytopathy, glomerulopathy,nephrotic syndrome, minimal change disease (MCD, e.g. minimal changenephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS),and/or diseases related or associated therewith, to pharmaceuticalcompositions and combinations comprising such active components, and tocertain therapeutic uses thereof.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing and/or reducing therisk of disturbance of podocyte function, podocyte loss or injury,and/or for use in protecting, preserving, improving, repairing orregenerating podocytes and/or their function.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing and/or reducing therisk of nephrotic syndrome either of primary or secondary cause (e.g.including steroid-resistant or steroid-refractory nephrotic syndrome),including minimal change disease (MCD, e.g. minimal change nephropathy,such as steroid hormone refractory minimal change nephropathy),membranous nephropathy (MN, e.g. membranous glomerulonephritis) and/orfocal segmental glomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing and/or reducing therisk of nephrotic syndrome (e.g. including steroid-resistant orsteroid-ref ractory nephrotic syndrome), minimal change disease (MCD,e.g. minimal change nephropathy, such as steroid hormone refractoryminimal change nephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing and/or reducing therisk of minimal change disease (MCD, e.g. minimal change nephropathy,such as steroid hormone refractory minimal change nephropathy),membranous nephropathy (MN, e.g. membranous glomerulonephritis) and/orfocal segmental glomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating and/or preventing metabolicdiseases, particularly diabetes, especially type 2 diabetes mellitus,and/or conditions related thereto (e.g. diabetic complications), in apatient (particularly human patient) with or at risk of podocyte relateddisorders, disturbance of podocyte function, podocyte loss or injury,glomerulopathy, nephrotic syndrome, minimal change disease (MCD, e.g.minimal change nephropathy, such as steroid hormone refractory minimalchange nephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating and/or preventing metabolicdiseases, particularly diabetes, especially type 2 diabetes mellitus,and/or conditions related thereto (e.g. diabetic complications), in apatient (particularly human patient) with or at risk of nephroticsyndrome (e.g. including steroid-resistant or steroid-refractorynephrotic syndrome), minimal change disease (MCD, e.g. minimal changenephropathy, such as steroid hormone refractory minimal changenephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating and/or preventing metabolicdiseases, particularly diabetes, especially type 2 diabetes mellitus,and/or conditions related thereto (e.g. diabetic complications), in apatient (particularly human patient) with or at risk of minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating and/or preventing metabolicdiseases, particularly diabetes, especially type 2 diabetes mellitus,and/or conditions related thereto (e.g. diabetic complications), in apatient (particularly human patient) with or at risk of membranousnephropathy (MN, e.g. membranous glomerulonephritis).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating and/or preventing metabolicdiseases, particularly diabetes, especially type 2 diabetes mellitus,and/or conditions related thereto (e.g. diabetic complications), in apatient (particularly human patient) with or at risk of focal segmentalglomerulosclerosis (FSGS).

Further, the present invention relates to a method of treating,preventing and/or reducing the likelihood or risk of nephrotic syndrome(e.g. including steroid-resistant or steroid-refractory nephroticsyndrome), minimal change disease (MCD, e.g. minimal change nephropathy,such as steroid hormone refractory minimal change nephropathy),membranous nephropathy (MN, e.g. membranous glomerulonephritis) and/orfocal segmental glomerulosclerosis (FSGS) in a patient (particularlyhuman patient) in need thereof, comprising administering an effectiveamount of a certain DPP-4 inhibitor (preferably linagliptin), optionallyin combination with one or more other active agents, to the patient.

Further, the present invention relates to a method of treating,preventing and/or reducing the likelihood or risk of minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS) in a patient (particularly human patient) in need thereof,comprising administering an effective amount of a certain DPP-4inhibitor (preferably linagliptin), optionally in combination with oneor more other active agents, to the patient.

Moreover, the present invention further relates to a certain DPP-4inhibitor (preferably linagliptin, and/or optionally in combination withone or more other active agents, such as e.g. one or more antidiabetics,optionally in combination with an ACE inhibitor and/or an ARB) for usein renoprotection and/or in treating, preventing, delaying the onset ofand/or delaying the progress of albuminuria, in a patient (particularlyhuman patient with diabetes, especially type 2 diabetes mellitus)suffering from nephropathy (diabetic nephropathy).

Moreover, the present invention further relates to a certain DPP-4inhibitor (preferably linagliptin, optionally in combination with one ormore other active agents, such as e.g. one or more antidiabetics, and/oroptionally in combination with an ACE inhibitor and/or an ARB) for usein renoprotection and/or in treating, preventing, reducing the riskand/or delaying the onset of podocyte related disorders, disturbance ofpodocyte function, podocyte loss or injury, podocytopathy,glomerulopathy, nephrotic syndrome, minimal change disease (MCD, e.g.minimal change nephropathy such as steroid hormone refractory minimalchange nephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS), ina patient (particularly human patient with diabetes, especially type 2diabetes mellitus) suffering from nephropathy (diabetic nephropathy)and/or albuminuria.

Moreover, the present invention further relates to a certain DPP-4inhibitor (preferably linagliptin, optionally in combination with one ormore other active agents, such as e.g. one or more antidiabetics, and/oroptionally in combination with an ACE inhibitor and/or an ARB) for usein renoprotection and/or in treating, preventing, delaying the onset ofand/or delaying the progress of albuminuria, in a patient (particularlyhuman patient with diabetes, especially type 2 diabetes mellitussuffering from diabetic nephropathy) with or at risk of risk of podocyterelated disorders, disturbance of podocyte function, podocyte loss orinjury, podocytopathy, glomerulopathy, nephrotic syndrome, minimalchange disease (MCD, e.g. minimal change nephropathy such as steroidhormone refractory minimal change nephropathy), membranous nephropathy(MN, e.g. membranous glomerulonephritis) and/or focal segmentalglomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in the treatment of diabetic nephropathy,particularly diabetic nephropathy with an elevated serum creatinine andproteinuria (>300 mg/day) in patients with type 2 diabetes.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in treating or lowering albuminuria or diabeticnephropathy on top of angiotensin-converting enzyme (ACE) inhibitortherapy and/or angiotensin II receptor blockade (ARB) therapy in type 2diabetes patients, particularly with diabetic nephropathy (e.g. earlydiabetic nephropathy).

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in a method of treating, preventing, reducing therisk of, delaying the onset or slowing the progression of albuminuria(micro- or macro-albuminuria) or diabetic nephropathy, preferably intype 2 diabetes patients, such as e.g. type 2 diabetes patients withearly diabetic nephropathy, especially in those patients on (e.g.previous or ongoing) therapy with an angiotensin-converting enzyme (ACE)inhibitor and/or an angiotensin II receptor blocker (ARB), e.g. patientswith inadequate control of albuminuria despite therapy with anangiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), particularly said method comprisingadministering the DPP-4 inhibitor in combination with theangiotensin-converting enzyme (ACE) inhibitor and/or the angiotensin IIreceptor blocker (ARB) to the patient.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents, such as e.g. including an ARB or ACE inhibitor, such ase.g. with or without additional standard background therapy such as e.g.with an ACEi or ARB) for use in preventing, reducing the risk orlikelihood of or delaying the onset or slowing the progression of renalmorbidity and/or mortality, preferably in type 2 diabetes patients.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in preventing, reducing the risk of or delayingthe onset or progression of micro- or macro-albuminuria, chronic kidneydisease (CKD), worsening of CKD, and/or acute renal failure, preferablyin type 2 diabetes patients.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in reducing the risk of or delaying the onset orthe progression of micro- or macro-albuminuria, the onset of chronickidney disease (CKD), the worsening of CKD, the onset of acute renalfailure and/or of death, preferably in type 2 diabetes patients.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in a method of preventing, reducing the risk ofor delaying the onset or progression of micro- or macro-albuminuria,chronic kidney disease (CKD), worsening of CKD, and/or acute renalfailure, preferably in type 2 diabetes patients, particularly type 2diabetes patients with early diabetic nephropathy, especially in thosepatients on (e.g. previous or ongoing) therapy with anangiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), such as e.g. patients with inadequate control ofalbuminuria despite therapy with an angiotensin-converting enzyme (ACE)inhibitor and/or an angiotensin II receptor blocker (ARB), particularlysaid method comprising administering the DPP-4 inhibitor in combinationwith the angiotensin-converting enzyme (ACE) inhibitor and/or theangiotensin II receptor blocker (ARB) to the patient.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin optionally in combination with one or more otheractive agents, such as e.g. one or more antidiabetics, and/or optionallyin combination with one or more further active agents, such as e.g. oneor more antiplatelet agents, antihypertensive and/or lipid loweringagents) for use in preventing, reducing the risk of or delaying theonset or slowing the progression of renal morbidity and/or mortality,such as preventing, reducing or delaying the onset or progression ofmicro- or macro-albuminuria, the onset of chronic kidney disease (CKD),the worsening of CKD, and/or the onset of acute renal failure and/or ofdeath, particularly in a human patient with diabetes, especially type 2diabetes mellitus; such as e.g. in a patient (particularly diabetespatient, especially type 2 diabetes mellitus patient) having renal-and/or cardiovascular-history and/or medications, such as diabeticnephropathy, macrovascular disease (e.g. coronary artery diasease,periperal artery disease, cerebrovascular disease, hypertension),microvascular disease (e.g. diabetic nephropathy, neuropathy,retinopathy), coronary artery disease, cerebrovascular disease,peripheral artery disease, hypertension, ex-smoker or current smoker,and/or on acetylsalicylic acid, antihypertensive and/or lipid loweringmedication, such as e.g. on (previous or ongoing) therapy withacetylsalicylic acid, an ACE inhibitor, ARB, beta-blocker,Calcium-antagonist or diuretic, or combination thereof, and/or on(previous or ongoing) therapy with a fibrate, niacin or statin, orcombination thereof.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin optionally in combination with one or more otheractive agents, such as e.g. one or more antidiabetics, and/or optionallyin combination with one or more further active agents, such as e.g. oneor more antiplatelet agents, antihypertensive and/or lipid loweringagents) for use in preventing, reducing the risk of or delaying theonset or slowing the progression of renal morbidity and/or mortality,such as preventing, reducing or delaying the onset or progression ofmicro- or macro-albuminuria, the onset of chronic kidney disease (CKD),the worsening of CKD, and/or the onset of acute renal failure and/or ofdeath, particularly in a human patient having diabetes, especially type2 diabetes mellitus, and/or for use in treating, lowering, preventing,reducing the risk of, delaying the onset or slowing the progression ofalbuminuria (micro- or macro-album inuria) or diabetic nephropathy,particularly in a human patient having diabetes, especially type 2diabetes mellitus; such as e.g. in a patient with diabetic nephropathy(with or without additional standard background therapy such as e.g.with an ACEi or ARB), e.g. including a vulnerable diabetic nephropathypatient such as who are aged 65 years typically having longer diabetesduration (>5 years), renal impairment (such as mild (60 to <90 eGFRml/min/1.73 m²) or moderate (30 to <60 eGFR ml/min/1.73 m²) renalimpairment) and/or higher baseline UACR (such as advanced stages ofmicro- or macroalbuminuria).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the expression of podocalyxin as a marker for podocyteintegrity in linagliptin-, enalapril- or vehicle-treated diabetic db/dbmice and in healthy control mice.

DETAILED DESCRIPTION OF THE INVENTION

Within the scope of the present invention it has now been found that acertain DPP-4 inhibitor (preferably linagliptin) as defined herein aswell as pharmaceutical combinations, compositions, uses or methodsaccording to this invention of that DPP-4 inhibitor (preferablylinagliptin) optionally in combination with one or more other activeagents as defined herein have properties, which make them suitable forthe purpose of this invention and/or for fulfilling one or more of theneeds mentioned herein.

DPP-4 is analogous to CD26 a T-cell antigene which plays a role inT-cell activation and immuno-modulation. Furthermore, linagliptin, aselective DPP-4 inhibitor further qualifies for the instant purposeswith certain anti-oxidative and/or anti-inflammatory features.

Further, samples from human kidneys indicate that proteinuric humandiseases (such as e.g. diabetic nephropathy or nephrotic syndrome) seemto be characterized by an upregulation of glomerular DPP-4.

Linagliptin has a positive effect on podocytes (which is a kidneyspecific cell population which is essential for the filtration integrityof the kidney). Linagliptin compensates or delays the loss ofpodocalyxin (a podocytic extracellular contact protein). Typically,diabetic nephropathy as well as nephrotic syndrome is characterized by adecrease of integral podocytic proteins. Therefore, linagliptin isuseful in the therapy and/or prophylaxis, such as e.g. treatment,prevention, protection, reducing the risk, delaying the onset and/orslowing the progression, of such conditions and/or related diseases, in(human) patients in need thereof (who may be with or without diabetes(e.g. type 2 diabetes), such as e.g. independently from or beyondglycemic control).

Thus, the present invention provides a certain DPP-4 inhibitor asdefined herein (preferably linagliptin, optionally in combination withone or more other active agents) for use in treating, preventing and/orreducing the risk of podocyte related disorders, disturbance of podocytefunction, podocyte loss or injury, podocytopathy, glomerulopathy,nephrotic syndrome, minimal change disease (MCD, e.g. minimal changenephropathy, such as steroid hormone refractory minimal changenephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS),and/or diseases related or associated therewith.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing and/or reducing therisk of podocyte related disorders, disturbance of podocyte function,podocyte loss or injury, and/or podocytopathy, and/or diseases relatedor associated therewith.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing or reducing thelikelihood or risk of nephrotic syndrome.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing or reducing thelikelihood or risk of minimal change disease (MCD, e.g. minimal changenephropathy, such as steroid hormone refractory minimal changenephropathy).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing or reducing thelikelihood or risk of membranous nephropathy (MN, e.g. membranousglomerulonephritis).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in treating, preventing or reducing thelikelihood or risk of focal segmental glomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in reducing mortality, morbidity, durationor frequency of hospitalization, in a patient with or at risk ofpodocyte related disorders and/or nephrotic syndrome, including minimalchange disease (MCD, e.g. minimal change nephropathy, such as steroidhormone refractory minimal change nephropathy), membranous nephropathy(MN, e.g. membranous glomerulonephritis) and/or focal segmentalglomerulosclerosis (FSGS).

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in the treatment of diabetic nephropathy,particularly diabetic nephropathy with an elevated serum creatinine andproteinuria (>300 mg/day) in patients with type 2 diabetes.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in treating or lowering albuminuria or diabeticnephropathy on top of angiotensin-converting enzyme (ACE) inhibitortherapy and/or angiotensin II receptor blockade (ARB) therapy in type 2diabetes patients, particularly with early diabetic nephropathy.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in a method of treating, preventing, reducing therisk of, delaying the onset or slowing the progression of albuminuria(micro- or macro-albuminuria) or diabetic nephropathy, preferably intype 2 diabetes patients, particularly type 2 diabetes patients withearly diabetic nephropathy, especially in those patients with inadequatecontrol of albuminuria despite therapy with an angiotensin-convertingenzyme (ACE) inhibitor and/or an angiotensin II receptor blocker (ARB),particularly said method comprising administering the DPP-4 inhibitor incombination with the angiotensin-converting enzyme (ACE) inhibitorand/or the angiotensin II receptor blocker (ARB) to the patient.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents, such as e.g. including an ARB or ACE inhibitor) for usein preventing, reducing the risk of or delaying the onset or slowing theprogression of renal morbidity and/or mortality, preferably in type 2diabetes patients.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in preventing, reducing the risk of or delayingthe onset or progression of micro- or macro-albuminuria, chronic kidneydisease (CKD), worsening of CKD, and/or acute renal failure, preferablyin type 2 diabetes patients.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in reducing the risk of or delaying the onset orthe progression of micro- or macro-albuminuria, the onset of chronickidney disease (CKD), the worsening of CKD, the onset of acute renalfailure and/or of death, preferably in type 2 diabetes patients.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents) for use in a method of preventing, reducing the risk ofor delaying the onset or progression of micro- or macro-albuminuria,chronic kidney disease (CKD), worsening of CKD, and/or acute renalfailure, preferably in type 2 diabetes patients, particularly type 2diabetes patients with early diabetic nephropathy, especially in thosepatients with inadequate control of albuminuria despite therapy with anangiotensin-converting enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB), particularly said method comprisingadministering the DPP-4 inhibitor in combination with theangiotensin-converting enzyme (ACE) inhibitor and/or the angiotensin IIreceptor blocker (ARB) to the patient.

Further, the present invention relates to a certain DPP-4 inhibitor,preferably linagliptin (optionally in combination with one or more otheractive agents, such as e.g. one or more antidiabetics, and/or optionallyin combination with one or more further active agents, such as e.g. oneor more antiplatelet agents, antihypertensive and/or lipid loweringagents) for use in preventing, reducing the risk of or delaying theonset or slowing the progression of renal morbidity and/or mortality,such as preventing, reducing or delaying the onset or progression ofmicro- or macro-albuminuria, the onset of chronic kidney disease (CKD),the worsening of CKD, and/or the onset of acute renal failure and/or ofdeath, particularly in a human patient with diabetes, especially type 2diabetes mellitus; such as e.g. in a patient (particularly diabetespatient, especially type 2 diabetes mellitus patient) having renal-and/or cardiovascular-history and/or medications, such as diabeticnephropathy, macrovascular disease (e.g. coronary artery diasease,periperal artery disease, cerebrovascular disease, hypertension),microvascular disease (e.g. diabetic nephropathy, neuropathy,retinopathy), coronary artery disease, cerebrovascular disease,peripheral artery disease, hypertension, ex-smoker or current smoker,and/or on acetylsalicylic acid, antihypertensive and/or lipid loweringmedication, such as e.g. on (ongoing) therapy with acetylsalicylic acid,an ACE inhibitor, ARB, beta-blocker, Calcium-antagonist or diuretic, orcombination thereof, and/or on (ongoing) therapy with a fibrate, niacinor statin, or combination thereof.

The present invention further provides a certain DPP-4 inhibitor asdefined herein (preferably linagliptin, optionally in combination withone or more other active agents) for use in for treating and/orpreventing metabolic diseases, particularly diabetes, especially type 2diabetes mellitus, and/or conditions related thereto (e.g. diabeticcomplications), in a patient (particularly human patient) with or atrisk of podocyte related disorders and/or nephrotic syndrome, includingminimal change disease (MCD, e.g. minimal change nephropathy, such assteroid hormone refractory minimal change nephropathy), membranousnephropathy (MN, e.g. membranous glomerulonephritis) and/or focalsegmental glomerulosclerosis (FSGS).

Examples of metabolic disorders or diseases amenable by the therapy ofthis invention may include, without being limited to, type 1 diabetes,type 2 diabetes, impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG), hyperglycemia, postprandial hyperglycemia,postabsorptive hyperglycemia, latent autoimmune diabetes in adults(LADA), overweight, obesity, dyslipidemia, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia, postprandiallipemia, hypertension, atherosclerosis, endothelial dysfunction,osteoporosis, chronic systemic inflammation, non alcoholic fatty liverdisease (NAFLD), retinopathy, neuropathy, nephropathy, nephroticsyndrome, polycystic ovarian syndrome, and/or metabolic syndrome.

The present invention further relates to a certain DPP-4 inhibitor(preferably linagliptin, optionally in combination with one or moreother active agents) for use in at least one of the following methods:

-   -   preventing, slowing the progression of, delaying the onset of or        treating a metabolic disorder or disease, such as e.g. type 1        diabetes mellitus, type 2 diabetes mellitus, impaired glucose        tolerance (IGT), impaired fasting blood glucose (IFG),        hyperglycemia, postprandial hyperglycemia, postabsorptive        hyperglycemia, latent autoimmune diabetes in adults (LADA),        overweight, obesity, dyslipidemia, hyperlipidemia,        hypercholesterolemia, hypertriglyceridemia, hyperNEFA-emia,        postprandial lipemia, hypertension, atherosclerosis, endothelial        dysfunction, osteoporosis, chronic systemic inflammation, non        alcoholic fatty liver disease (NAFLD), retinopathy, neuropathy,        nephropathy, nephrotic syndrome, polycystic ovarian syndrome,        and/or metabolic syndrome;    -   improving and/or maintaining glycemic control and/or for        reducing of fasting plasma glucose, of postprandial plasma        glucose, of postabsorptive plasma glucose and/or of glycosylated        hemoglobin HbA1c, or preventing, reducing the risk of, slowing        the progression of, delaying the onset of or treating worsening        or deterioration of glycemic control, need for insulin therapy        or elevated HbA1c despite treatment;    -   preventing, slowing, delaying the onset of or reversing        progression from pre-diabetes, impaired glucose tolerance (IGT),        impaired fasting blood glucose (IFG), insulin resistance and/or        from metabolic syndrome to type 2 diabetes mellitus;    -   preventing, reducing the risk of, slowing the progression of,        delaying the onset of or treating of complications of diabetes        mellitus such as micro- and macrovascular diseases, such as        nephropathy, micro- or macroalbuminuria, proteinuria, nephrotic        syndrome, retinopathy, cataracts, neuropathy, learning or memory        impairment, neurodegenerative or cognitive disorders, cardio- or        cerebrovascular diseases, tissue ischaemia, diabetic foot or        ulcus, atherosclerosis, hypertension, endothelial dysfunction,        myocardial infarction, acute coronary syndrome, unstable angina        pectoris, stable angina pectoris, peripheral arterial occlusive        disease, cardiomyopathy, heart failure, heart rhythm disorders,        vascular restenosis, and/or stroke;    -   reducing body weight and/or body fat and/or liver fat and/or        intra-myocellular fat or preventing an increase in body weight        and/or body fat and/or liver fat and/or intra-myocellular fat or        facilitating a reduction in body weight and/or body fat and/or        liver fat and/or intra-myocellular fat;    -   preventing, slowing, delaying the onset of or treating the        degeneration of pancreatic beta cells and/or the decline of the        functionality of pancreatic beta cells and/or for improving,        preserving and/or restoring the functionality of pancreatic beta        cells and/or stimulating and/or restoring or protecting the        functionality of pancreatic insulin secretion;    -   preventing, slowing, delaying the onset of or treating non        alcoholic fatty liver disease (NAFLD) including hepatic        steatosis, non-alcoholic steatohepatitis (NASH) and/or liver        fibrosis (such as e.g. preventing, slowing the progression,        delaying the onset of, attenuating, treating or reversing        hepatic steatosis, (hepatic) inflammation and/or an abnormal        accumulation of liver fat);    -   preventing, slowing the progression of, delaying the onset of or        treating type 2 diabetes with failure to conventional        antidiabetic mono- or combination therapy;    -   achieving a reduction in the dose of conventional antidiabetic        medication required for adequate therapeutic effect;    -   reducing the risk for adverse effects associated with        conventional antidiabetic medication (e.g. hypoglycemia or        weight gain); and/or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;

in a patient in need thereof (such as e.g. a patient as describedherein, for example a human patient having diabetes), and/or

particularly in a patient (particularly human patient) with or at riskof podocyte related disorders, disturbance of podocyte function,podocyte loss or injury, podocytopathy, glomerulopathy, nephroticsyndrome, minimal change disease (MCD, e.g. minimal change nephropathy,such as steroid hormone refractory minimal change nephropathy),membranous nephropathy (MN, e.g. membranous glomerulonephritis) and/orfocal segmental glomerulosclerosis (FSGS).

In an embodiment, the patient with or at risk of podocyte relateddisorders, disturbance of podocyte function, podocyte loss or injury,podocytopathy, glomerulopathy, nephrotic syndrome, minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS) as described herein is diabetic.

In another embodiment, the patient with or at risk of podocyte relateddisorders, disturbance of podocyte function, podocyte loss or injury,podocytopathy, glomerulopathy, nephrotic syndrome, minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS) as described herein is non-diabetic.

In a further embodiment, the patient described herein is a subjecthaving diabetes (e.g. type 1 or type 2 diabetes or LADA, particularlytype 2 diabetes).

In particular, the subject within this invention may be a human, e.g.human child, a human adolescent or, particularly, a human adult.

Accordingly, in a particular embodiment, a preferred DPP-4 inhibitorwithin the meaning of this invention is linagliptin.

Pharmaceutical compositions or combinations for use in these therapies(treatments or preventions) comprising a certain DPP-4 inhibitor(preferably linagliptin) as defined herein optionally together with oneor more other active agents are also contemplated.

Further, the present invention relates to a certain DPP-4 inhibitor(preferably linagliptin), optionally in combination with one, two ormore further active agents, each as defined herein, for use in thetherapies (treatments or preventions) as described herein.

Further, the present invention relates to the use of a certain DPP-4inhibitor (preferably linagliptin), optionally in combination with one,two or more further active agents, each as defined herein, for preparinga pharmaceutical composition which is suitable for the treatment and/orprevention purposes of this invention.

Further, the present invention relates to a therapeutic (treatment orprevention) method as described herein, said method comprisingadministering an effective amount of a certain DPP-4 inhibitor(preferably linagliptin) and, optionally, one or more other active ortherapeutic agents to the patient in need thereof, each as describedherein.

Other aspects of the present invention become apparent to the skilledperson from the foregoing and following remarks (including the examplesand claims).

The aspects of the present invention, in particular the pharmaceuticalcompounds, compositions, combinations, methods and uses, refer to acertain DPP-4 inhibitor (preferably linagliptin), optionally incombination with one or more other active agents, as definedhereinbefore and hereinafter.

Type 2 diabetes mellitus is a common chronic and progressive diseasearising from a complex pathophysiology involving the dual endocrineeffects of insulin resistance and impaired insulin secretion with theconsequence not meeting the required demands to maintain plasma glucoselevels in the normal range. This leads to chronic hyperglycaemia and itsassociated micro- and macrovascular complications or chronic damages,such as e.g. diabetic nephropathy, retinopathy or neuropathy, ormacrovascular (e.g. cardio- or cerebro-vascular) complications. Thevascular disease component plays a significant role, but is not the onlyfactor in the spectrum of diabetes associated disorders. The highfrequency of complications leads to a significant reduction of lifeexpectancy. Diabetes is currently the most frequent cause of adult-onsetloss of vision, renal failure, and amputation in the IndustrialisedWorld because of diabetes induced complications and is associated with atwo to five fold increase in cardiovascular disease risk.

Furthermore, diabetes (particularly type 2 diabetes) is often coexistentand interrelated with obesity and these two conditions together impose aparticularly complex therapeutic challenge. Because of the effects ofobesity on insulin resistance, weight loss and its maintainance is animportant therapeutic objective in overweight or obese individuals withprediabetes, metabolic syndrome or diabetes. Studies have beendemonstrated that weight reduction in subjects with type 2 diabetes isassociated with descreased insulin resistance, improved measures ofglycemia and lipemia, and reduced blood pressure. Maintainance of weightreduction over longer term is considered to improve glycemic control andprevent diabetic complications (e.g. reduction of risk forcardiovascular diseases or events). Thus, weight loss is recommended forall overweight or obese indivuduals who have or are at risk fordiabetes. However, obese patients with type 2 diabetes have much greaterdifficulty losing weight and maintain the reduced weight than thegeneral non-diabetic population.

Overweight may be defined as the condition wherein the individual has abody mass index (BMI) greater than or 25 kg/m² and less than 30 kg/m².The terms “overweight” and “pre-obese” are used interchangeably.

Obesity may be also defined as the condition wherein the individual hasa BMI equal to or greater than 30 kg/m². According to a WHO definitionthe term obesity may be categorized as follows: class I obesity is thecondition wherein the BMI is equal to or greater than 30 kg/m² but lowerthan 35 kg/m²; class II obesity is the condition wherein the BMI isequal to or greater than 35 kg/m² but lower than 40 kg/m²; class IIIobesity (extreme obesity) is the condition wherein the BMI is equal toor greater than 40 kg/m². Obesity may include e.g. visceral or abdominalobesity.

Visceral obesity may be defined as the condition wherein a waist-to-hipratio of greater than or equal to 1.0 in men and 0.8 in women ismeasured. It defines the risk for insulin resistance and the developmentof pre-diabetes.

Abdominal obesity may usually be defined as the condition wherein thewaist circumference is >40 inches or 102 cm in men, and is >35 inches or94 cm in women. With regard to a Japanese ethnicity or Japanese patientsabdominal obesity may be defined as waist circumference 85 cm in men and90 cm in women (see e.g. investigating committee for the diagnosis ofmetabolic syndrome in Japan).

The treatment of type 2 diabetes typically begins with diet andexercise, followed by oral antidiabetic monotherapy, and althoughconventional monotherapy may initially control blood glucose in somepatients, it is however associated with a high secondary failure rate.The limitations of single-agent therapy for maintaining glycemic controlmay be overcome, at least in some patients, and for a limited period oftime by combining multiple drugs to achieve reductions in blood glucosethat cannot be sustained during long-term therapy with single agents.Available data support the conclusion that in most patients with type 2diabetes current monotherapy will fail and treatment with multiple drugswill be required.

But, because type 2 diabetes is a progressive disease, even patientswith good initial responses to conventional combination therapy willeventually require an increase of the dosage or further treatment withinsulin because the blood glucose level is very difficult to maintainstable for a long period of time. Although existing combination therapyhas the potential to enhance glycemic control, it is not withoutlimitations (especially with regard to long term efficacy). Further,traditional therapies may show an increased risk for side effects, suchas hypoglycemia or weight gain, which may compromise their efficacy andacceptability.

Thus, for many patients, these existing drug therapies result inprogressive deterioration in metabolic control despite treatment and donot sufficiently control metabolic status especially over long-term andthus fail to achieve and to maintain glycemic control in advanced,progressed or late stage type 2 diabetes, including diabetes withinadequate glycemic control despite conventional oral and/or non-oralantidiabetic medication.

Therefore, although intensive treatment of hyperglycemia can reduce theincidence of chronic damages, many patients with diabetes remaininadequately treated, partly because of limitations in long termefficacy, tolerability and dosing inconvenience of conventionalantihyperglycemic therapies.

In addition, obesity, overweight or weight gain (e.g. as side or adverseeffect of some conventional antidiabetic medications) furthercomplicates the treatment of diabetes and its microvascular ormacrovascular complications.

This high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and makrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cerebro- orcardiovascular complications such as e.g. myocardial infarction, strokeor vascular mortality or morbidity) in patients with diabetes.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and α-glucosidaseinhibitors. Non-oral (typically injected) antidiabetic drugsconventionally used in therapy (such as e.g. first- or second-line,and/or mono- or (initial or add-on) combination therapy) include,without being restricted thereto, GLP-1 or GLP-1 analogues, and insulinor insulin analogues.

However, the use of these conventional antidiabetic or antihyperglycemicagents can be associated with various adverse effects. For example,metformin can be associated with lactic acidosis or gastrointestinalside effects; sulfonylureas, glinides and insulin or insulin analoguescan be associated with hypoglycemia and weight gain; thiazolidinedionescan be associated with edema, bone fracture, weight gain and heartfailure/cardiac effects; and alpha-glucosidase blockers and GLP-1 orGLP-1 analogues can be associated with gastrointestinal adverse effects(e.g. dyspepsia, flatulence or diarrhea, or nausea or vomiting).

Therefore, it remains a need in the art to provide efficacious, safe andtolerable antidiabetic therapies.

Further, within the therapy of type 2 diabetes, it is a need fortreating the condition effectively, avoiding the complications inherentto the condition, and delaying disease progression, e.g. in order toachieve a long-lasting therapeutic benefit.

Furthermore, it remains a need that antidiabetic treatments not onlyprevent the long-term complications often found in advanced stages ofdiabetes disease, but also are a therapeutic option in those diabetespatients who have developed or are at risk of developing complications,such as renal impairment.

Moreover, it remains a need to provide prevention or reduction of riskfor adverse effects associated with conventional antidiabetic therapies.

The enzyme DPP-4 (dipeptidyl peptidase IV) also known as CD26 is aserine protease known to lead to the cleavage of a dipeptide from theN-terminal end of a number of proteins having at their N-terminal end aprolin or alanin residue. Due to this property DPP-4 inhibitorsinterfere with the plasma level of bioactive peptides including thepeptide GLP-1 and are considered to be promising drugs for the treatmentof diabetes mellitus.

For example, DPP-4 inhibitors and their uses are disclosed in WO2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769,WO2007/014886; WO 2004/050658, WO 2004/111051, WO 2005/058901, WO2005/097798; WO 2006/068163, WO 2007/071738, WO 2008/017670; WO2007/128721, WO 2007/128724, WO 2007/128761, or WO 2009/121945.

In the monitoring of the treatment of diabetes mellitus the HbA1c value,the product of a non-enzymatic glycation of the haemoglobin B chain, isof exceptional importance. As its formation depends essentially on theblood sugar level and the life time of the erythrocytes the HbA1c in thesense of a “blood sugar memory” reflects the average blood sugar levelof the preceding 4-12 weeks. Diabetic patients whose HbA1c level hasbeen well controlled over a long time by more intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample) aresignificantly better protected from diabetic microangiopathy. Theavailable treatments for diabetes can give the diabetic an averageimprovement in their HbA1c level of the order of 1.0-1.5%. Thisreduction in the HbA1C level is not sufficient in all diabetics to bringthem into the desired target range of <7.0%, preferably <6.5% and morepreferably <6% HbA1c.

Within the meaning of this invention, inadequate or insufficientglycemic control means in particular a condition wherein patients showHbA1c values above 6.5%, in particular above 7.0%, even more preferablyabove 7.5%, especially above 8%. An embodiment of patients withinadequate or insufficient glycemic control include, without beinglimited to, patients having a HbA1c value from 7.5 to 10% (or, inanother embodiment, from 7.5 to 11%). A special sub-embodiment ofinadequately controlled patients refers to patients with poor glycemiccontrol including, without being limited, patients having a HbA1c value9%.

Within glycemic control, in addition to improvement of the HbA1c level,other recommended therapeutic goals for type 2 diabetes mellituspatients are improvement of fasting plasma glucose (FPG) and ofpostprandial plasma glucose (PPG) levels to normal or as near normal aspossible. Recommended desired target ranges of preprandial (fasting)plasma glucose are 70-130 mg/dL (or 90-130 mg/dL) or <110 mg/dL, and oftwo-hour postprandial plasma glucose are <180 mg/dL or <140 mg/dL.

In one embodiment, diabetes patients within the meaning of thisinvention may include patients who have not previously been treated withan antidiabetic drug (drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in naïve patients. In anotherembodiment, diabetes patients within the meaning of this invention mayinclude patients with advanced or late stage type 2 diabetes mellitus(including patients with failure to conventional antidiabetic therapy),such as e.g. patients with inadequate glycemic control on one, two ormore conventional oral and/or non-oral antidiabetic drugs as definedherein, such as e.g. patients with insufficient glycemic control despite(mono-)therapy with metformin, a thiazolidinedione (particularlypioglitazone), a sulphonylurea, a glinide, GLP-1 or GLP-1 analogue,insulin or insulin analogue, or an α-glucosidase inhibitor, or despitedual combination therapy with metformin/sulphonylurea,metformin/thiazolidinedione (particularly pioglitazone),sulphonylurea/α-glucosidase inhibitor, pioglitazone/sulphonylurea,metformin/insulin, pioglitazone/insulin or sulphonylurea/insulin. Thus,in an embodiment, the therapies described herein may be used in patientsexperienced with therapy, e.g. with conventional oral and/or non-oralantidiabetic mono- or dual or triple combination medication as mentionedherein.

A further embodiment of diabetic patients within the meaning of thisinvention refers to patients ineligible for metformin therapy including

-   -   patients for whom metformin therapy is contraindicated, e.g.        patients having one or more contraindications against metformin        therapy according to label, such as for example patients with at        least one contraindication selected from:    -   renal disease, renal impairment or renal dysfunction (e.g., as        specified by product information of locally approved metformin),        dehydration,    -   unstable or acute congestive heart failure,    -   acute or chronic metabolic acidosis, and    -   hereditary galactose intolerance;        and    -   patients who suffer from one or more intolerable side effects        attributed to metformin, particularly gastrointestinal side        effects associated with metformin, such as for example patients        suffering from at least one gastrointestinal side effect        selected from:    -   nausea,    -   vomiting,    -   diarrhoea,    -   intestinal gas, and    -   severe abdominal discomfort.

A further embodiment of the diabetes patients which may be amenable tothe therapies of this invention may include, without being limited,those diabetes patients for whom normal metformin therapy is notappropriate, such as e.g. those diabetes patients who need reduced dosemetformin therapy due to reduced tolerability, intolerability orcontraindication against metformin or due to (mildly) impaired/reducedrenal function (including elderly patients, such as e.g. ≥60-65 years).

A further embodiment of patients (e.g. which may be diabetic ornon-diabetic) within the meaning of this invention refers to patientshaving renal disease, renal dysfunction, or insufficiency or impairmentof renal function (including mild, moderate and severe renalimpairment), e.g. as suggested by elevated serum creatinine levels (e.g.serum creatinine levels above the upper limit of normal for their age,e.g. ≥130-150 μmol/l, or 1.5 mg/dl (≥136 μmol/l) in men and ≥1.4 mg/dl(≥124 μmol/l) in women) or abnormal creatinine clearance (e.g.glomerular filtration rate (GFR)≤30-60 ml/min).

In this context, for more detailed example, mild renal impairment may bee.g. suggested by a creatinine clearance of 50-80 ml/min (approximatelycorresponding to serum creatine levels of ≤1.7 mg/dL in men and ≤1.5mg/dL in women); moderate renal impairment may be e.g. suggested by acreatinine clearance of 30-50 ml/min (approximately corresponding toserum creatinine levels of >1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5mg/dL in women); and severe renal impairment may be e.g. suggested by acreatinine clearance of <30 ml/min (approximately corresponding to serumcreatinine levels of >3.0 mg/dL in men and >2.5 mg/dL in women).Patients with end-stage renal disease require dialysis (e.g.hemodialysis or peritoneal dialysis).

For other more detailed example, patients with renal disease, renaldysfunction or renal impairment include patients with chronic renalinsufficiency or impairment, which can be stratified according toglomerular filtration rate (GFR, ml/min/1.73 m²) into 5 disease stages:stage 1 characterized by normal GFR≥90 plus either persistentalbuminuria or known structural or hereditary renal disease; stage 2characterized by mild reduction of GFR (GFR 60-89) describing mild renalimpairment; stage 3 characterized by moderate reduction of GFR (GFR30-59) describing moderate renal impairment; stage 4 characterized bysevere reduction of GFR (GFR 15-29) describing severe renal impairment;and terminal stage 5 characterized by requiring dialysis or GFR<15describing established kidney failure (end-stage renal disease, ESRD).

A further embodiment of patients (e.g. which may be diabetic ornon-diabetic) within the meaning of this invention refers to diabetespatients with or at risk of developing renal complications, such asdiabetic nephropathy (including chronic and progressive renalinsufficiency, albuminuria, proteinuria, fluid retention in the body(edema) and/or hypertension).

In certain embodiments, the patients which may be amenable to thetherapies of this invention may have or are at-risk of one or more ofthe following diseases, disorders or conditions: type 1 diabetes, type 2diabetes, impaired glucose tolerance (IGT), impaired fasting bloodglucose (IFG), hyperglycemia, postprandial hyperglycemia, postabsorptivehyperglycemia, latent autoimmune diabetes in adults (LADA), overweight,obesity, dyslipidemia (including e.g. atherogenic dyslipidemia),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,hyperNEFA-emia, postprandial lipemia, hypertension, atherosclerosis,endothelial dysfunction, osteoporosis, chronic systemic inflammation,non alcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome,hyperuricemia, metabolic syndrome, nephropathy, micro- ormacroalbuminuria, proteinuria, nephrotic syndrome, retinopathy,cataracts, neuropathy, learning or memory impairment, neurodegenerativeor cognitive disorders, cardio- or cerebrovascular diseases, tissueischaemia, diabetic foot or ulcus, atherosclerosis, hypertension,endothelial dysfunction, myocardial infarction, acute coronary syndrome,unstable angina pectoris, stable angina pectoris, peripheral arterialocclusive disease, cardiomyopathy (including e.g. uremiccardiomyopathy), heart failure, cardiac hypertrophy, heart rhythmdisorders, vascular restenosis, stroke, (renal, cardiac, cerebral orhepatic) ischemia/reperfusion injuries, (renal, cardiac, cerebral orhepatic) fibrosis, (renal, cardiac, cerebral or hepatic) vascularremodelling; a diabetic disease, e.g. type 2 diabetes mellitus being(with or without obesity) being particularly to be noted (e.g. as anunderlying disease).

In a further embodiment, the patients with or at-risk of SIRS/sepsiswhich may be amenable to the therapies of this invention have a diabeticdisease, such as e.g. type 2 diabetes mellitus, and, optionally, mayhave or are at-risk of one or more other diseases, disorders orconditions, such as e.g. selected from those mentioned immediatelyabove.

Accordingly, the present invention thus relates to a certain DPP-4inhibitor as defined herein, preferably linagliptin (BI 1356), for usein the therapies (treatments and/or preventions) described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination withmetformin, for use in the therapies (treatments and/or preventions)described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination withpioglitazone, for use in the therapies (treatments and/or preventions)described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination withtelmisartan, for use in the therapies (treatments and/or preventions)described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination with aGLP-1 receptor agonist (such as e.g. exenatide, exenatide LAR,liraglutide, taspoglutide, semaglutide, albiglutide, lixisenatide,dulaglutide, or native GLP-1) for use in the therapies (treatmentsand/or preventions) described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination with aninsulin or insulin analogue (e.g. basal insulin, such as e.g. insulinglargin, insulin detemir or insulin degludec, or NPH insulin) for use inthe therapies (treatments and/or preventions) described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination with adiuretic, an ARB and/or an ACE inhibitor for use in the therapies(treatments and/or preventions) described herein. The present inventionfurther relates to a certain DPP-4 inhibitor as defined herein,preferably linagliptin (BI 1356), in combination with a corticosteroidfor use in the therapies (treatments and/or preventions) describedherein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination withone or more other active agents, e.g. selected from other antidiabeticsubstances, active substances that lower the blood sugar level, activesubstances that lower the lipid level in the blood, active substancesthat raise the HDL level in the blood, active substances that lowerblood pressure, and active substances that are indicated in thetreatment of atherosclerosis or obesity, for use in the therapies(treatments and/or preventions) described herein.

The present invention further relates to a certain DPP-4 inhibitor asdefined herein, preferably linagliptin (BI 1356), in combination withone or more other antidiabetics selected from the group consisting ofmetformin, a sulphonylurea, nateglinide, repaglinide, athiazolidinedione, a PPAR-gamma-agonist, an alpha-glucosidase inhibitor,insulin or an insulin analogue, and GLP-1 or a GLP-1 analogue,optionally in combination with one or more further active agents (e.g.selected from a diuretic, ACE inhibitor and/or ARB, such as e.g.telmisartan), for use in the therapies (treatments and/or preventions)described herein.

The present invention further relates to a pharmaceutical compositioncomprising a certain DPP-4 inhibitor as defined herein, preferablylinagliptin (BI 1356), for use in the therapies described herein.

The present invention further relates to a pharmaceutical compositioncomprising a certain DPP-4 inhibitor as defined herein, preferablylinagliptin (BI 1356), and metformin, for use in the therapies describedherein.

The present invention further relates to a pharmaceutical compositioncomprising a certain DPP-4 inhibitor as defined herein, preferablylinagliptin (BI 1356), and pioglitazone, for use in the therapiesdescribed herein.

The present invention further relates to a combination comprising acertain DPP-4 inhibitor (particularly linagliptin) and one or more otheractive agents selected from those mentioned herein, e.g. selected fromother antidiabetic substances, active substances that lower the bloodsugar level, active substances that lower the lipid level in the blood,active substances that raise the HDL level in the blood, activesubstances that lower blood pressure, active substances that areindicated in the treatment of atherosclerosis or obesity, e.g. each asdescribed herein; particularly for simultaneous, separate or sequentialuse in the therapies described herein.

The present invention further relates to a combination comprising acertain DPP-4 inhibitor (particularly linagliptin) and one or more otherantidiabetics selected from the group consisting of metformin, asulphonylurea, nateglinide, repaglinide, a thiazolidinedione, aPPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or aninsulin analogue, and GLP-1 or a GLP-1 analogue, particularly forsimultaneous, separate or sequential use in the therapies describedherein, optionally in combination with a diuretic, ACE inhibitor and/orARB, such as e.g. telmisartan.

The present invention further relates to therapies or therapeutic orpreventive methods or uses as described herein, such as e.g. to a methodfor treating and/or preventing a metabolic disease, such as e.g. type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications) comprising administering (e.g. simultaneously, separatelyor sequentially) an effective amount of a certain DPP-4 inhibitor(particularly linagliptin) as defined herein and, optionally, one ormore other active agents, such as e.g. one or more other antidiabeticsselected from the group consisting of metformin, a sulphonylurea,nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma-agonist, analpha-glucosidase inhibitor, insulin or an insulin analogue, and GLP-1or a GLP-1 analogue,

optionally in combination with one or more further active agents (e.g. adiuretic, ACE inhibitor and/or ARB, such as e.g. telmisartan), to thepatient (particularly human patient) in need thereof, such as e.g. apatient as described herein, including a patient with or at risk ofpodocyte related disorders, disturbance of podocyte function, podocyteloss or injury, podocytopathy, glomerulopathy, nephrotic syndrome,minimal change disease (MCD, e.g. minimal change nephropathy, such assteroid hormone refractory minimal change nephropathy), membranousnephropathy (MN, e.g. membranous glomerulonephritis) and/or focalsegmental glomerulosclerosis (FSGS).

The present invention further relates to therapies or therapeutic orpreventive methods or uses as described herein, such as e.g. a methodfor treating and/or preventing a metabolic disease, such as e.g. type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), comprising administering an effective amount oflinagliptin (BI 1356) and metformin, and optionally one or more furtheractive agents, to the patient (particularly human patient) in needthereof, such as e.g. a patient as described herein, including a patientwith or at risk of podocyte related disorders, disturbance of podocytefunction, podocyte loss or injury, podocytopathy, glomerulopathy,nephrotic syndrome, minimal change disease (MCD, e.g. minimal changenephropathy, such as steroid hormone refractory minimal changenephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).

The present invention further relates to therapies or therapeutic orpreventive methods or uses as described herein, such as e.g. a methodfor treating and/or preventing a metabolic disease, such as e.g. type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), comprising administering an effective amount oflinagliptin (BI 1356) and pioglitazone, and optionally one or morefurther active agents, to the patient (particularly human patient) inneed thereof, such as e.g. a patient as described herein, including apatient with or at risk of podocyte related disorders, disturbance ofpodocyte function, podocyte loss or injury, podocytopathy,glomerulopathy, nephrotic syndrome, minimal change disease (MCD, e.g.minimal change nephropathy, such as steroid hormone refractory minimalchange nephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).

The present invention further relates to therapies or therapeutic orpreventive methods or uses as described herein, such as e.g. a methodfor treating and/or preventing a metabolic disease, such as e.g. type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), comprising administering an effective amount oflinagliptin (BI 1356) and telmisartan, and optionally one or morefurther active agents, to the patient (particularly human patient) inneed thereof, such as e.g. a patient as described herein, including apatient with or at risk of podocyte related disorders, disturbance ofpodocyte function, podocyte loss or injury, podocytopathy,glomerulopathy, nephrotic syndrome, minimal change disease (MCD, e.g.minimal change nephropathy, such as steroid hormone refractory minimalchange nephropathy), membranous nephropathy (MN, e.g. membranousglomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).

The present invention further relates to therapies or therapeutic orpreventive methods or uses as described herein, such as e.g. a methodfor treating and/or preventing a metabolic disease, such as e.g. type 2diabetes mellitus and/or conditions related thereto (e.g. diabeticcomplications), comprising administering an effective amount oflinagliptin (BI 1356) and an insulin or insulin analogue (such as e.g. abasal insulin), and optionally one or more further active agents, to thepatient (particularly human patient) in need thereof, such as e.g. apatient as described herein, including a patient with or at risk ofpodocyte related disorders, disturbance of podocyte function, podocyteloss or injury, podocytopathy, glomerulopathy, nephrotic syndrome,minimal change disease (MCD, e.g. minimal change nephropathy, such assteroid hormone refractory minimal change nephropathy), membranousnephropathy (MN, e.g. membranous glomerulonephritis) and/or focalsegmental glomerulosclerosis (FSGS).

Further, the present invention relates to a method of treating,preventing and/or reducing the risk of podocyte related disorders,disturbance of podocyte function, podocyte loss or injury,podocytopathy, glomerulopathy, nephrotic syndrome, minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS) in a patient (particularly a human patient, who may suffer fromdiabetes, e.g. type 1 or type 2 diabetes or LADA, particularly type 2diabetes, or who may be non-diabetic) in need thereof, comprisingadministering an effective amount of linagliptin, optionally incombination with one or more other active agents (including activesubstances which are indicated in the treatment of nephrotic syndrome,such as e.g. selected from corticosteroids (e.g. prednisone orprednisolone), diuretics, ACE inhibitors, ARBs such as e.g. telmisartan,cyclophosphamide, cyclosporine, and/or anticoagulants), to the patient.

Further, the present invention relates to a method of treating,preventing and/or reducing the risk of podocyte related disorders,disturbance of podocyte function, podocyte loss or injury,podocytopathy, glomerulopathy, nephrotic syndrome, minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS) in a patient (particularly a human patient, who may suffer fromdiabetes, e.g. type 1 or type 2 diabetes or LADA, particularly type 2diabetes, or who may be non-diabetic) in need thereof, comprisingadministering an effective amount of linagliptin, optionally incombination with one or more other active agents, e.g. selected fromother antidiabetic substances, active substances that lower the bloodsugar level, active substances that lower the lipid level in the blood,active substances that raise the HDL level in the blood, activesubstances that lower blood pressure, active substances that areindicated in the treatment of atherosclerosis or obesity, and/or activesubstances which are indicated in the treatment of nephrotic syndrome,to the patient.

Further, the present invention relates to a method of treating,preventing and/or reducing the risk of podocyte related disorders,disturbance of podocyte function, podocyte loss or injury,podocytopathy, glomerulopathy, nephrotic syndrome, minimal changedisease (MCD, e.g. minimal change nephropathy, such as steroid hormonerefractory minimal change nephropathy), membranous nephropathy (MN, e.g.membranous glomerulonephritis) and/or focal segmental glomerulosclerosis(FSGS) in a patient (particularly a human patient, who may suffer fromdiabetes, e.g. type 1 or type 2 diabetes or LADA, particularly type 2diabetes, or who may be non-diabetic) in need thereof, comprisingadministering an effective amount of linagliptin and one or more otherantidiabetics selected from the group consisting of metformin, asulphonylurea, nateglinide, repaglinide, a thiazolidinedione, aPPAR-gamma-agonist, an alpha-glucosidase inhibitor, insulin or aninsulin analogue, and GLP-1 or a GLP-1 analogue, optionally incombination with one or more further active agents (e.g. an activesubstance which is indicated in the treatment of nephrotic syndrome,such as a corticosteroid (e.g. prednisone or prednisolone), a diuretic,ACE inhibitor, ARB such as e.g. telmisartan, cyclophosphamide,cyclosporine, and/or an anticoagulant), to the patient.

A DPP-4 inhibitor within the meaning of the present invention includes,without being limited to, any of those DPP-4 inhibitors mentionedhereinabove and hereinbelow, preferably orally and/or subcutaneouslyactive DPP-4 inhibitors.

In a first embodiment (embodiment A), a DPP-4 inhibitor in the contextof the present invention is any DPP-4 inhibitor of formula (I)

or formula (II)

or formula (III)

or formula (IV)

wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl,(quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl,(4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl,(3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl,(4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyland R2 denotes 3-(R)-amino-piperidin-1-yl,(2-amino-2-methyl-propyl)-methylamino or(2-(S)-amino-propyl)-methylamino,or its pharmaceutically acceptable salt.

Regarding the first embodiment (embodiment A), preferred DPP-4inhibitors are any or all of the following compounds and theirpharmaceutically acceptable salts:

-   1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(142)):

-   1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(252)):

-   1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2004/018468, example 2(80)):

-   2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one    (compare WO 2004/050658, example 136):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(1)):

-   1-[(3-Cyano-quinolin-211)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(30)):

-   1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(39)):

-   1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine    (compare WO 2006/029769, example 2(4)):

-   1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(52)):

-   1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(81)):

-   1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(82)):

-   1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine    (compare WO 2005/085246, example 1(83)):

These DPP-4 inhibitors are distinguished from structurally comparableDPP-4 inhibitors, as they combine exceptional potency and a long-lastingeffect with favourable pharmacological properties, receptor selectivityand a favourable side-effect profile or bring about unexpectedtherapeutic advantages or improvements when combined with otherpharmaceutical active substances. Their preparation is disclosed in thepublications mentioned.

In a second embodiment (embodiment B), a DPP-4 inhibitor in the contextof the present invention is a DPP-4 inhibitor selected from the groupconsisting of sitagliptin, vildagliptin, saxagliptin, alogliptin,gemigliptin,

-   (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,-   (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,-   (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,-   (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,-   (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,-   (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,-   5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic    acid bis-dimethylamide,-   3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine,-   [(2R)-1-{[(3R)-pyrrolidin-3-ylamino]acetyl}pyrrolidin-2-yl]boronic    acid,-   (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile,-   2-({6-[(3R)-3-amino-3-methylpiperidin-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidin-5-yl}methyl)-4-fluorobenzonitrile,-   6-[(3R)-3-amino-piperidin-1-yl]-5-(2-chloro-5-fluoro-benzyl)-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione,    and-   (S)-2-methylpyrazolo[1,5-a]primidine-6-carboxylic acid    {2-[(2-cyanopyrrolidin-1-yl)-2-oxoethylamino]-2-methylpropyl}amide,    or its pharmaceutically acceptable salt.

A more preferred DPP-4 inhibitor among the abovementioned DPP-4inhibitors of embodiment A of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,particularly the free base thereof (which is also known as linagliptinor BI 1356).

Preferably the DPP-4 inhibitor of this invention is selected from thegroup consisting of linagliptin, sitagliptin, vildagliptin, alogliptin,saxagliptin, teneligliptin, anagliptin, gemigliptin and dutogliptin, ora pharmaceutically acceptable salt of one of the herein mentioned DPP-4inhibitors, or a prodrug thereof.

A particularly preferred DPP-4 inhibitor to be emphasized within thepresent invention is linagliptin. The term “linagliptin” as employedherein refers to linagliptin or a pharmaceutically acceptable saltthereof, including hydrates and solvates thereof, and crystalline formsthereof, preferably linagliptin refers to1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.Crystalline forms are described in WO 2007/128721. Methods for themanufacture of linagliptin are described in the patent applications WO2004/018468 and WO 2006/048427 for example. Linagliptin is distinguishedfrom structurally comparable DPP-4 inhibitors, as it combinesexceptional potency and a long-lasting effect with favourablepharmacological properties, receptor selectivity and a favourableside-effect profile or bring about unexpected therapeutic advantages orimprovements in mono- or dual or triple combination therapy.

For avoidance of any doubt, the disclosure of each of the foregoing andfollowing documents cited above in connection with the specified DPP-4inhibitors is specifically incorporated herein by reference in itsentirety.

An embodiment of this invention refers to a DPP-4 inhibitor suitable foruse in the treatment and/or prevention of metabolic diseases(particularly type 2 diabetes mellitus) in patients, wherein saidpatients further suffering from renal disease, renal dysfunction orrenal impairment, particularly characterized in that said DPP-4inhibitor is administered to said patients in the same dose levels as topatients with normal renal function, thus e.g. said DPP-4 inhibitor doesnot require downward dosing adjustment for impaired renal function.

For example, a DPP-4 inhibitor according to this invention (especiallyone which may be suited for patients with impaired renal function) maybe such an oral DPP-4 inhibitor, which and whose active metabolites havepreferably a relatively wide (e.g. about >100 fold) therapeutic windowand/or, especially, that are primarily eliminated via hepatic metabolismor biliary excretion (preferably without adding additional burden to thekidney).

In more detailed example, a DPP-4 inhibitor according to this invention(especially one which may be suited for patients with impaired renalfunction) may be such an orally administered DPP-4 inhibitor, which hasa relatively wide (e.g. >100 fold) therapeutic window (preferably asafety profile comparable to placebo) and/or which fulfils one or moreof the following pharmacokinetic properties (preferably at itstherapeutic oral dose levels):

-   -   The DPP-4 inhibitor is substantially or mainly excreted via the        liver (e.g. >80% or even >90% of the administered oral dose),        and/or for which renal excretion represents no substantial or        only a minor elimination pathway (e.g. <10%, preferably <7%, of        the administered oral dose measured, for example, by following        elimination of a radiolabelled carbon (¹⁴C) substance oral        dose);    -   The DPP-4 inhibitor is excreted mainly unchanged as parent drug        (e.g. with a mean of >70%, or >80%, or, preferably, 90% of        excreted radioactivity in urine and faeces after oral dosing of        radiolabelled carbon (¹⁴C) substance), and/or which is        eliminated to a non-substantial or only to a minor extent via        metabolism (e.g. <30%, or <20%, or, preferably, 10%);    -   The (main) metabolite(s) of the DPP-4 inhibitor is/are        pharmacologically inactive. Such as e.g. the main metabolite        does not bind to the target enzyme DPP-4 and, optionally, it is        rapidly eliminated compared to the parent compound (e.g. with a        terminal half-life of the metabolite of 20 h, or, preferably,        about 16 h, such as e.g. 15.9 h).

In one embodiment, the (main) metabolite in plasma (which may bepharmacologically inactive) of a DPP-4 inhibitor having a3-amino-piperidin-1-yl substituent is such a derivative where the aminogroup of the 3-amino-piperidin-1-yl moiety is replaced by a hydroxylgroup to form the 3-hydroxy-piperidin-1-yl moiety (e.g. the3-(S)-hydroxy-piperidin-1-yl moiety, which is formed by inversion of theconfiguration of the chiral center).

Further properties of a DPP-4 inhibitor according to this invention maybe one or more of the following: Rapid attainment of steady state (e.g.reaching steady state plasma levels (>90% of the steady state plasmaconcentration) between second and fifth day of treatment withtherapeutic oral dose levels), little accumulation (e.g. with a meanaccumulation ratio R_(A,AUC)≤1.4 with therapeutic oral dose levels),and/or preserving a long-lasting effect on DPP-4 inhibition, preferablywhen used once-daily (e.g. with almost complete (>90%) DPP-4 inhibitionat therapeutic oral dose levels, >80% inhibition over a 24 h intervalafter once-daily intake of therapeutic oral drug dose), significantdecrease in 2 h postprandial blood glucose excursions by ≥80% (alreadyon first day of therapy) at therapeutic dose levels, and cumulativeamount of unchanged parent compound excreted in urine on first day beingbelow 1% of the administered dose and increasing to not more than about3-6% in steady state.

Thus, for example, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor has a primarily non-renalroute of excretion, i.e. said DPP-4 inhibitor is excreted to anon-substantial or only to a minor extent (e.g. <10%, preferably <7%,e.g. about 5%, of administered oral dose, preferably of oral therapeuticdose) via the kidney (measured, for example, by following elimination ofa radiolabelled carbon (¹⁴C) substance oral dose).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted substantially ormainly via the liver, bile or faeces (measured, for example, byfollowing elimination of a radiolabelled carbon (¹⁴C) substance oraldose).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor is excreted mainly unchangedas parent drug (e.g. with a mean of >70%, or >80%, or, preferably, 90%of excreted radioactivity in urine and faeces after oral dosing ofradiolabelled carbon (¹⁴C) substance),

said DPP-4 inhibitor is eliminated to a non-substantial or only to aminor extent via metabolism, and/or

the main metabolite of said DPP-4 inhibitor is pharmacologicallyinactive or has a relatively wide therapeutic window.

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor does not significantly impairglomerular and/or tubular function of a type 2 diabetes patient withchronic renal insufficiency (e.g. mild, moderate or severe renalimpairment or end stage renal disease), and/or

said DPP-4 inhibitor trough levels in the blood plasma of type 2diabetes patients with mild or moderate renal impairment are comparableto the levels in patients with normal renal function, and/or

said DPP-4 inhibitor does not require to be dose-adjusted in a type 2diabetes patient with impaired renal function (e.g. mild, moderate orsevere renal impairment or end stage renal disease, preferablyregardless of the stage of renal impairment).

Further, a DPP-4 inhibitor according to this invention may becharacterized in that said DPP-4 inhibitor provides its minimallyeffective dose at that dose that results in >50% inhibition of DPP-4activity at trough (24 h after last dose) in >80% of patients, and/orsaid DPP-4 inhibitor provides its fully therapeutic dose at that dosethat results in >80% inhibition of DPP-4 activity at trough (24 h afterlast dose) in >80% of patients.

Further, a DPP-4 inhibitor according to this invention may becharacterized in that being suitable for use in type 2 diabetes patientswho are with diagnosed renal impairment or complication and/or who areat risk of developing renal complications, e.g. patients with or at riskof diabetic nephropathy (including chronic and progressive renalinsufficiency, albuminuria, proteinuria, fluid retention in the body(edema) and/or hypertension).

GLP-1 receptor agonists include, without being limited, exogenous GLP-1(natural or synthetic), GLP-1 mimetics or analogues (including longeracting analogues which are resistant to or have reduced susceptibilityto enzymatic degradation by DPP-4 and NEP 24.11) and other substances(whether peptidic or non-peptidic, e.g. small molecules) which promotesignalling through the GLP-1 receptor.

Examples of GLP-1 analogues may include (group G2): exenatide (syntheticexendin-4, e.g. formulated as Byetta®); exenatide LAR (long actingrelease formulation of exenatide, e.g. formulated as Bydureon®);liraglutide (e.g. formulated as Victoza®); taspoglutide; semaglutide;albiglutide (e.g. formulated as Syncria); lixisenatide; dulaglutide; andthe di-PEGylated GLP-1 compound comprising the amino acid sequence ofthe pegylated SEQ ID NO:1, wherein Xaa at position 2 is D-Ala, Gly, Val,Leu, Ile, Ser or Thr; Xaa at position 16 is Gly, Glu, Asp or Lys; andXaa at position 27 is Val or Ile, and wherein one PEG molecule iscovalently attached to the Cys residue at position 39 [[Cys₄₅]] and onePEG molecule is covelently attached to the Cys residue at position 40[[Cys₄₆-NH₂]], wherein each of the PEG molecules used for PEGylationreaction is a 20,000 dalton linear methoxy PEG maleimide. Preferably theGLP-1 consists of the amino acid sequence of SQ ID NO:2.

Preferred examples of GLP-1 receptor agonists (GLP-1 analogues) of thisinvention are exenatide, exenatide LAR, liraglutide, taspoglutide,semaglutide, albiglutide, lixisenatide and dulaglutide.

GLP-1 analogues have typically significant sequence identity to GLP-1(e.g. greater than 50%, 75%, 90% or 95%) and may be derivatised, e.g. byconjunction to other proteins (e.g. albumin or IgG-Fc fusion protein) orthrough chemical modification.

In an embodiment, the GLP-1 receptor agonist is preferably administeredby injection (preferably subcutaneously).

Unless otherwise noted, according to this invention it is to beunderstood that the definitions of the active agents (including theDPP-4 inhibitors and GLP-1 receptor agonists) mentioned hereinabove andherein below may also contemplate their pharmaceutically acceptablesalts, and prodrugs, hydrates, solvates and polymorphic forms thereof.Particularly the terms of the therapeutic agents given herein refer tothe respective active drugs. With respect to salts, hydrates andpolymorphic forms thereof, particular reference is made to those whichare referred to herein.

An effective amount of a compound as used herein means an amountsufficient to cure, alleviate or partially arrest the clinicalmanifestations of a given state or condition, such as a disease ordisorder, and its complications. An amount adequate to accomplish thisis defined as “effective amount”. Effective amounts for each purposewill depend on the severity of the condition, disease or injury as wellas the weight and general state of the subject and mode ofadministration, or the like. It will be understood that determining anappropriate dosage may be achieved using routine experimentation, e.g.by constructing a matrix of values and testing different points in thematrix, which is all within the ordinary skills of a trained physicianor veterinary.

In the present context, treatment or treating mean the management andcare of a patient or subject for the purpose of combating a condition, adisease or a disorder. The term is intended to include the full spectrumof treatments for a given condition from which the patient or subject issuffering, such as administration of the active compound to alleviatethe symptoms or complications, to delay the progression of the disease,disorder or condition, to alleviate or relief the symptoms andcomplications, to improve patient's status or outcome, and/or to cure oreliminate the disease, disorder or condition as well as to prevent thecondition, wherein prevention is to be understood as the management andcare of a patient for the purpose of combating the disease, condition,or disorder and includes the administration of the active compounds toprevent or delay the onset of the symptoms or complications.

Within this invention it is to be understood that the combinations,compositions or combined uses according to this invention may envisagethe simultaneous, sequential or separate administration of the activecomponents or ingredients.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits) and uses, such as e.g. the simultaneous,sequential or separate use of the components or ingredients.

The combined administration of this invention may take place byadministering the active components or ingredients together, such ase.g. by administering them simultaneously in one single or in twoseparate formulations or dosage forms. Alternatively, the administrationmay take place by administering the active components or ingredientssequentially, such as e.g. successively in two separate formulations ordosage forms.

For the combination therapy of this invention the active components oringredients may be administered separately (which implies that they areformulated separately) or formulated altogether (which implies that theyare formulated in the same preparation or in the same dosage form).Hence, the administration of one element of the combination of thepresent invention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

With respect to embodiment A, the methods of synthesis for the DPP-4inhibitors according to embodiment A of this invention are known to theskilled person. Advantageously, the DPP-4 inhibitors according toembodiment A of this invention can be prepared using synthetic methodsas described in the literature. Thus, for example, purine derivatives offormula (I) can be obtained as described in WO 2002/068420, WO2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, thedisclosures of which are incorporated herein. Purine derivatives offormula (II) can be obtained as described, for example, in WO2004/050658 or WO 2005/110999, the disclosures of which are incorporatedherein. Purine derivatives of formula (III) and (IV) can be obtained asdescribed, for example, in WO 2006/068163, WO 2007/071738 or WO2008/017670, the disclosures of which are incorporated herein. Thepreparation of those DPP-4 inhibitors, which are specifically mentionedhereinabove, is disclosed in the publications mentioned in connectiontherewith. Polymorphous crystal modifications and formulations ofparticular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO2007/128724, respectively, the disclosures of which are incorporatedherein in their entireties. Formulations of particular DPP-4 inhibitorswith metformin or other combination partners are described in WO2009/121945, the disclosure of which is incorporated herein in itsentirety.

Typical dosage strengths of the dual fixed combination (tablet) oflinagliptin/metformin IR (immediate release) are 2.5/500 mg, 2.5/850 mgand 2.5/1000 mg, which may be administered 1-3 times a day, particularlytwice a day.

Typical dosage strengths of the dual fixed combination (tablet) oflinagliptin/metformin XR (extended release) are 5/500 mg, 5/1000 mg and5/1500 mg (each one tablet) or 2.5/500 mg, 2.5/750 mg and 2.5/1000 mg(each two tablets), which may be administered 1-2 times a day,particularly once a day, preferably to be taken in the evening withmeal.

The present invention further provides a DPP-4 inhibitor as definedherein for use in (add-on or initial) combination therapy with metformin(e.g. in a total daily amount from 500 to 2000 mg metforminhydrochloride, such as e.g. 500 mg, 850 mg or 1000 mg once or twicedaily).

With respect to embodiment B, the methods of synthesis for the DPP-4inhibitors of embodiment B are described in the scientific literatureand/or in published patent documents, particularly in those citedherein.

The elements of the combination of this invention may be administered byvarious ways, for example by oral, buccal, sublingual, enterical,parenteral (e.g., transdermal, intramuscular or subcutaneous),inhalative (e.g., liquid or powder inhalation, aerosol), pulmonary,intranasal (e.g. spray), intraperitoneal, vaginal, rectal, or topicalroutes of administration and may be formulated, alone or together, insuitable dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

In an embodiment, the DPP-4 inhibitor according to the invention ispreferably administered orally.

Suitable doses and dosage forms of the DPP-4 inhibitors may bedetermined by a person skilled in the art and may include thosedescribed herein or in the relevant references.

For pharmaceutical application in warm-blooded vertebrates, particularlyhumans, the compounds of this invention are usually used in dosages from0.001 to 100 mg/kg body weight, preferably at 0.01-15 mg/kg or 0.1-15mg/kg, in each case 1 to 4 times a day. For this purpose, the compounds,optionally combined with other active substances, may be incorporatedtogether with one or more inert conventional carriers and/or diluents,e.g. with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, cetylstearyl alcohol, carboxymethylcelluloseor fatty substances such as hard fat or suitable mixtures thereof intoconventional galenic preparations such as plain or coated tablets,capsules, powders, suspensions or suppositories.

The pharmaceutical compositions according to this invention comprisingthe DPP-4 inhibitors as defined herein are thus prepared by the skilledperson using pharmaceutically acceptable formulation excipients asdescribed in the art and appropriate for the desired route ofadministration. Examples of such excipients include, without beingrestricted to diluents, binders, carriers, fillers, lubricants, flowpromoters, crystallisation retardants, disintegrants, solubilizers,colorants, pH regulators, surfactants and emulsifiers.

Oral formulations or dosage forms of the DPP-4 inhibitor of thisinvention may be prepared according to known techniques.

A pharmaceutical composition or dosage form (e.g. oral tablet) of aDPP-4 inhibitor according to embodiment A of the invention may typicallycontain as excipients (in addition to an active ingredient), forexample: one or more diluents, a binder, a disintegrant, and alubricant, preferably each as disclosed herein-below. In an embodiment,the disintegrant may be optional.

Examples of suitable diluents for compounds according to embodiment Ainclude cellulose powder, calcium hydrogen phosphate, erythritol, lowsubstituted hydroxypropyl cellulose, mannitol, pregelatinized starch orxylitol.

Examples of suitable lubricants for compounds according to embodiment Ainclude talc, polyethyleneglycol, calcium behenate, calcium stearate,hydrogenated castor oil or magnesium stearate.

Examples of suitable binders for compounds according to embodiment Ainclude copovidone (copolymerisates of vinylpyrrolidon with othervinylderivates), hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone),pregelatinized starch, or low-substituted hydroxypropylcellulose(L-HPC).

Examples of suitable disintegrants for compounds according to embodimentA include corn starch or crospovidone.

Suitable methods of preparing (oral) preparations or dosage forms of theDPP-4 inhibitors according to embodiment A of the invention are

-   -   direct tabletting of the active substance in powder mixtures        with suitable tabletting excipients;    -   granulation with suitable excipients and subsequent mixing with        suitable excipients and subsequent tabletting as well as film        coating; or    -   packing of powder mixtures or granules into capsules.

Suitable granulation methods are

-   -   wet granulation in the intensive mixer followed by fluidised bed        drying;    -   one-pot granulation;    -   fluidised bed granulation; or    -   dry granulation (e.g. by roller compaction) with suitable        excipients and subsequent tabletting or packing into capsules.

An exemplary composition (e.g. tablet core) of a DPP-4 inhibitoraccording to embodiment A of the invention comprises the first diluentmannitol, pregelatinized starch as a second diluent with additionalbinder properties, the binder copovidone, the disintegrant corn starch,and magnesium stearate as lubricant; wherein copovidone and/or cornstarch may be optional.

A tablet of a DPP-4 inhibitor according to embodiment A of the inventionmay be film coated, preferably the film coat compriseshydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG), talc,titanium dioxide and iron oxide (e.g. red and/or yellow).

In a further embodiment, the DPP-4 inhibitor according to the inventionmay be administered by injection (preferably subcutaneously). In anotherembodiment, the GLP-1 receptor agonist is preferably administered byinjection (preferably subcutaneously) as well.

Injectable formulations of the GLP-1 receptor agonist and/or the DPP-4inhibitor of this invention (particularly for subcutaneous use) may beprepared according to known formulation techniques, e.g. using suitableliquid carriers, which usually comprise sterile water, and, optionally,further additives such as e.g. preservatives, pH adjusting agents,buffering agents, isotoning agents, solubility aids and/or tensides orthe like, to obtain injectable solutions or suspensions. In addition,injectable formulations may comprise further additives, for examplesalts, solubility modifying agents or precipitating agents which retardrelease of the drug(s). In further addition, injectable GLP-1formulations may comprise GLP-1 stabilizing agents (e.g. a surfactant).

For example, an injectable formulation (particularly for subcutaneoususe) containing the GLP-1 receptor agonist (e.g. exenatide), optionallytogether with the DPP-4 inhibitor of this invention, may furthercomprise the following additives: a tonicity-adjusting agent (such ase.g. mannitol), an antimicrobial preservative (such as e.g. metacresol),a buffer or pH adjusting agent (such as e.g. glacial acetic acid andsodium acetate trihydrate in water for injection as a buffering solutionat pH 4.5), and optionally a solubilizing and/or stabilizing agent (suchas e.g. a surfactant or detergent).

In a further embodiment, the DPP-4 inhibitor according to the inventionmay be administered by a transdermal delivery system. In anotherembodiment, the GLP-1 receptor agonist is preferably administered by atransdermal delivery system as well.

Transdermal formulations (e.g. for transdermal patches or gels) of theGLP-1 receptor agonist and/or the DPP-4 inhibitor of this invention maybe prepared according to known formulation techniques, e.g. usingsuitable carriers and, optionally, further additives. To facilitatetransdermal passage, different methodologies and systems may be used,such as e.g. techniques involving formation of microchannels ormicropores in the skin, such as e.g. iontophoresis (based on low-levelelectrical current), sonophoresis (based on low-frequency ultrasound) ormicroneedling, or the use of drug-carrier agents (e.g. elastic or lipidvesicles such as transfersomes) or permeation enhancers.

For further details on dosage forms, formulations and administration ofDPP-4 inhibitors of this invention and/or GLP-1 receptor agonist of thisinvention, reference is made to scientific literature and/or publishedpatent documents, particularly to those cited herein.

The pharmaceutical compositions (or formulations) may be packaged in avariety of ways. Generally, an article for distribution includes one ormore containers that contain the one or more pharmaceutical compositionsin an appropriate form. Tablets are typically packed in an appropriateprimary package for easy handling, distribution and storage and forassurance of proper stability of the composition at prolonged contactwith the environment during storage. Primary containers for tablets maybe bottles or blister packs.

A suitable bottle, e.g. for a pharmaceutical composition or combination(tablet) comprising a DPP-4 inhibitor according to embodiment A of theinvention, may be made from glass or polymer (preferably polypropylene(PP) or high density polyethylene (HD-PE)) and sealed with a screw cap.The screw cap may be provided with a child resistant safety closure(e.g. press-and-twist closure) for preventing or hampering access to thecontents by children. If required (e.g. in regions with high humidity),by the additional use of a desiccant (such as e.g. bentonite clay,molecular sieves, or, preferably, silica gel) the shelf life of thepackaged composition can be prolonged.

A suitable blister pack, e.g. for a pharmaceutical composition orcombination (tablet) comprising a DPP-4 inhibitor according toembodiment A of the invention, comprises or is formed of a top foil(which is breachable by the tablets) and a bottom part (which containspockets for the tablets). The top foil may contain a metallic foil,particularly aluminium or aluminium alloy foil (e.g. having a thicknessof 20 μm to 45 μm, preferably 20 μm to 25 μm) that is coated with aheat-sealing polymer layer on its inner side (sealing side). The bottompart may contain a multi-layer polymer foil (such as e.g. poly(vinylchloride) (PVC) coated with poly(vinylidene choride) (PVDC); or a PVCfoil laminated with poly(chlorotriflouroethylene) (PCTFE)) or amulti-layer polymer-metal-polymer foil (such as e.g. a cold-formablelaminated PVC/aluminium/polyamide composition). Examples of blisterpacks may include alu/alu, alu/PVC/polyvinylacetate copolymer-acrylateor alu/PVC/PCTFE/PVC blisters.

To ensure a long storage period especially under hot and wet climateconditions an additional overwrap or pouch made of a multi-layerpolymer-metal-polymer foil (e.g. a laminatedpolyethylene/aluminium/polyester composition) may be used for theblister packs. Supplementary desiccant (such as e.g. bentonite clay,molecular sieves, or, preferably, silica gel) in this pouch package mayprolong the shelf life even more under such harsh conditions.

Solutions for injection may be available in typical suitablepresentation forms such as vials, cartridges or prefilled (disposable)pens, which may be further packaged.

The article may further comprise a label or package insert, which referto instructions customarily included in commercial packages oftherapeutic products, that may contain information about theindications, usage, dosage, administration, contraindications and/orwarnings concerning the use of such therapeutic products. In oneembodiment, the label or package inserts indicates that the compositioncan be used for any of the purposes described herein.

With respect to the first embodiment (embodiment A), the dosagetypically required of the DPP-4 inhibitors mentioned herein inembodiment A when administered intravenously is 0.1 mg to 10 mg,preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day. Thus,e.g. the dosage of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthinewhen administered orally is 0.5 mg to 10 mg per patient per day,preferably 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.

For example, doses of linagliptin when administered subcutaneously ori.v. for human patients are in the range of 0.3-10 mg, preferably from 1to 5 mg, particularly 2.5 mg, per patient per day.

In a further embodiment, for example, doses of linagliptin whenadministered subcutaneously for human patients (such as e.g. in obesehuman patients or for treating obesity) are in the range of 0.1-30 mg,preferably from 1 to 10 mg, particularly 5 mg, per patient per day.

A dosage form prepared with a pharmaceutical composition comprising aDPP-4 inhibitor mentioned herein in embodiment A contain the activeingredient in a dosage range of 0.1-100 mg. Thus, e.g. particular oraldosage strengths of1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthineare 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.

With respect to the second embodiment (embodiment B), the doses of DPP-4inhibitors mentioned herein in embodiment B to be administered tomammals, for example human beings, of, for example, approximately 70 kgbody weight, may be generally from about 0.5 mg to about 350 mg, forexample from about 10 mg to about 250 mg, preferably 20-200 mg, morepreferably 20-100 mg, of the active moiety per person per day, or fromabout 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day,divided preferably into 1 to 4 single doses which may, for example, beof the same size. Single oral dosage strengths comprise, for example,10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor activemoiety.

An oral dosage strength of the DPP-4 inhibitor sitagliptin is usuallybetween 25 and 200 mg of the active moiety. A recommended dose ofsitagliptin is 100 mg calculated for the active moiety (free baseanhydrate) once daily. Unit dosage strengths of sitagliptin free baseanhydrate (active moiety) are 25, 50, 75, 100, 150 and 200 mg.Particular unit dosage strengths of sitagliptin (e.g. per tablet) are25, 50 and 100 mg. An equivalent amount of sitagliptin phosphatemonohydrate to the sitagliptin free base anhydrate is used in thepharmaceutical compositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75,and 257 mg, respectively. Adjusted dosages of 25 and 50 mg sitagliptinare used for patients with renal failure. Typical dosage strengths ofthe dual combination of sitagliptin/metformin are 50/500 mg and 50/1000mg.

An oral dosage range of the DPP-4 inhibitor vildagliptin is usuallybetween 10 and 150 mg daily, in particular between 25 and 150 mg, 25 and100 mg or 25 and 50 mg or 50 and 100 mg daily. Particular examples ofdaily oral dosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. Ina more particular aspect, the daily administration of vildagliptin maybe between 25 and 150 mg or between 50 and 100 mg. In another moreparticular aspect, the daily administration of vildagliptin may be 50 or100 mg. The application of the active ingredient may occur up to threetimes a day, preferably one or two times a day. Particular dosagestrengths are 50 mg or 100 mg vildagliptin. Typical dosage strengths ofthe dual combination of vildagliptin/metformin are 50/850 mg and 50/1000mg.

Alogliptin may be administered to a patient at an oral daily dose ofbetween 5 mg/day and 250 mg/day, optionally between 10 mg and 200 mg,optionally between 10 mg and 150 mg, and optionally between 10 mg and100 mg of alogliptin (in each instance based on the molecular weight ofthe free base form of alogliptin). Thus, specific oral dosage amountsthat may be used include, but are not limited to 10 mg, 12.5 mg, 20 mg,25 mg, 50 mg, 75 mg and 100 mg of alogliptin per day. Alogliptin may beadministered in its free base form or as a pharmaceutically acceptablesalt.

Saxagliptin may be administered to a patient at an oral daily dose ofbetween 2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg.Specific oral dosage amounts that may be used include, but are notlimited to 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and100 mg of saxagliptin per day. Typical dosage strengths of the dualcombination of saxagliptin/metformin are 2.5/500 mg and 2.5/1000 mg.

A special embodiment of the DPP-4 inhibitors of this invention refers tothose orally administered DPP-4 inhibitors which are therapeuticallyefficacious at low dose levels, e.g. at oral dose levels <100 mg or <70mg per patient per day, preferably <50 mg, more preferably <30 mg or <20mg, even more preferably from 1 mg to 10 mg, particularly from 1 mg to 5mg (more particularly 5 mg), per patient per day (if required, dividedinto 1 to 4 single doses, particularly 1 or 2 single doses, which may beof the same size, preferentially, administered orally once- or twicedaily (more preferentially once-daily), advantageously, administered atany time of day, with or without food. Thus, for example, the daily oralamount 5 mg BI 1356 can be given in an once daily dosing regimen (i.e. 5mg BI 1356 once daily) or in a twice daily dosing regimen (i.e. 2.5 mgBI 1356 twice daily), at any time of day, with or without food.

The dosage of the active ingredients in the combinations andcompositions in accordance with the present invention may be varied,although the amount of the active ingredients shall be such that asuitable dosage form is obtained. Hence, the selected dosage and theselected dosage form shall depend on the desired therapeutic effect, theroute of administration and the duration of the treatment. Dosage rangesfor the combination may be from the maximal tolerated dose for thesingle agent to lower doses.

A particularly preferred DPP-4 inhibitor to be emphasized within themeaning of this invention is1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine(also known as BI 1356 or linagliptin). BI 1356 exhibits high potency,24 h duration of action, and a wide therapeutic window. In patients withtype 2 diabetes receiving multiple oral doses of 1, 2.5, 5 or 10 mg ofBI 1356 once daily for 12 days, BI 1356 shows favourable pharmacodynamicand pharmacokinetic profile (see e.g. Table 3 below) with rapidattainment of steady state (e.g. reaching steady state plasma levels(>90% of the pre-dose plasma concentration on Day 13) between second andfifth day of treatment in all dose groups), little accumulation (e.g.with a mean accumulation ratio R_(A,AUC)≤1.4 with doses above 1 mg) andpreserving a long-lasting effect on DPP-4 inhibition (e.g. with almostcomplete (>90%) DPP-4 inhibition at the 5 mg and 10 mg dose levels, i.e.92.3 and 97.3% inhibition at steady state, respectively, and >80%inhibition over a 24 h interval after drug intake), as well assignificant decrease in 2 h postprandial blood glucose excursions by 80%(already on Day 1) in doses 2.5 mg, and with the cumulative amount ofunchanged parent compound excreted in urine on Day 1 being below 1% ofthe administered dose and increasing to not more than about 3-6% on Day12 (renal clearance CL_(R,ss) is from about 14 to about 70 mL/min forthe administered oral doses, e.g. for the 5 mg dose renal clearance isabout 70 ml/min). In people with type 2 diabetes BI 1356 shows aplacebo-like safety and tolerability. With low doses of about 5 mg, BI1356 acts as a true once-daily oral drug with a full 24 h duration ofDPP-4 inhibition. At therapeutic oral dose levels, BI 1356 is mainlyexcreted via the liver and only to a minor extent (about <7% of theadministered oral dose) via the kidney. BI 1356 is primarily excretedunchanged via the bile. The fraction of BI 1356 eliminated via thekidneys increases only very slightly over time and with increasing dose,so that there will likely be no need to modify the dose of BI 1356 basedon the patients' renal function. The non-renal elimination of BI 1356 incombination with its low accumulation potential and broad safety marginmay be of significant benefit in a patient population that has a highprevalence of renal insufficiency and diabetic nephropathy.

TABLE 3 Geometric mean (gMean) and geometric coefficient of variation(gCV) of pharmacokinetic parameters of BI 1356 at steady state (Day 12)1 mg 2.5 mg 5 mg 10 mg Parameter gMean (gCV) gMean (gCV) gMean (gCV)gMean (gCV) AUC₀₋₂₄ 40.2 (39.7) 85.3 (22.7) 118 (16.0) 161 (15.7) [nmol· h/L] AUC_(T,ss) 81.7 (28.3) 117 (16.3) 158 (10.1) 190 (17.4) [nmol ·h/L] C_(max) [nmol/L] 3.13 (43.2) 5.25 (24.5) 8.32 (42.4) 9.69 (29.8)C_(max,ss) 4.53 (29.0) 6.58 (23.0) 11.1 (21.7) 13.6 (29.6) [nmol/L]t_(max)* [h] 1.50 [1.00-3.00] 2.00 [1.00-3.00] 1.75 [0.92-6.02] 2.00[1.50-6.00] t_(max,ss)* [h] 1.48 [1.00-3.00] 1.42 [1.00-3.00] 1.53[1.00-3.00] 1.34 [0.50-3.00] T_(1/2,ss) [h] 121 (21.3) 113 (10.2) 131(17.4) 130 (11.7) Accumulation 23.9 (44.0) 12.5 (18.2) 11.4 (37.4) 8.59(81.2) t_(1/2), [h] R_(A,Cmax) 1.44 (25.6) 1.25 (10.6) 1.33 (30.0) 1.40(47.7) R_(A,AUC) 2.03 (30.7) 1.37 (8.2) 1.33 (15.0) 1.18 (23.4) fe₀₋₂₄[%] NC 0.139 (51.2) 0.453 (125) 0.919 (115) fe_(T,ss) [%] 3.34 (38.3)3.06 (45.1) 6.27 (42.2) 3.22 (34.2) CL_(R,ss) 14.0 (24.2) 23.1 (39.3) 70(35.0) 59.5 (22.5) [mL/min] *median and range [min-max] NC notcalculated as most values below lower limit of quantification

As different metabolic functional disorders often occur simultaneously,it is quite often indicated to combine a number of different activeprinciples with one another. Thus, depending on the functional disordersdiagnosed, improved treatment outcomes may be obtained if a DPP-4inhibitor is combined with one or more active substances customary forthe respective disorders, such as e.g. one or more active substancesselected from among the other antidiabetic substances, especially activesubstances that lower the blood sugar level or the lipid level in theblood, raise the HDL level in the blood, lower blood pressure or areindicated in the treatment of atherosclerosis or obesity.

The DPP-4 inhibitors mentioned above—besides their use inmono-therapy—may also be used in conjunction with other activesubstances, by means of which improved treatment results can beobtained. Such a combined treatment may be given as a free combinationof the substances or in the form of a fixed combination, for example ina tablet or capsule. Pharmaceutical formulations of the combinationpartner needed for this may either be obtained commercially aspharmaceutical compositions or may be formulated by the skilled manusing conventional methods. The active substances which may be obtainedcommercially as pharmaceutical compositions are described in numerousplaces in the prior art, for example in the list of drugs that appearsannually, the “Rote Liste®” of the federal association of thepharmaceutical industry, or in the annually updated compilation ofmanufacturers' information on prescription drugs known as the“Physicians' Desk Reference”.

Examples of antidiabetic combination partners are metformin;sulphonylureas such as glibenclamide, tolbutamide, glimepiride,glipizide, gliquidon, glibornuride and gliclazide; nateglinide;repaglinide; mitiglinide; thiazolidinediones such as rosiglitazone andpioglitazone; PPAR gamma modulators such as metaglidases; PPAR-gammaagonists such as e.g. rivoglitazone, mitoglitazone, INT-131 andbalaglitazone; PPAR-gamma antagonists; PPAR-gamma/alpha modulators suchas tesaglitazar, muraglitazar, aleglitazar, indeglitazar and KRP297;PPAR-gamma/alpha/delta modulators such as e.g. lobeglitazone;AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2)inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors;pancreatic beta cell GCRP agonists such as GPR119 agonists(SMT3-receptor-agonists), such as the GPR119 agonists5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidineor5-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ylmethoxy]-2-(4-methanesulfonyl-phenyl)-pyridine;11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidaseblockers such as acarbose, voglibose and miglitol; alpha2-antagonists;insulin and insulin analogues such as human insulin, insulin lispro,insulin glusilin, r-DNA-insulinaspart, NPH insulin, insulin detemir,insulin degludec, insulin tregopil, insulin zinc suspension and insulinglargin; Gastric inhibitory Peptide (GIP); amylin and amylin analogues(e.g. pramlintide or davalintide); GLP-1 and GLP-1 analogues such asExendin-4, e.g. exenatide, exenatide LAR, liraglutide, taspoglutide,lixisenatide (AVE-0010), LY-2428757 (a PEGylated version of GLP-1),dulaglutide (LY-2189265), semaglutide or albiglutide; SGLT2-inhibitorssuch as e.g. dapagliflozin, sergliflozin (KGT-1251), atigliflozin,canagliflozin, ipragliflozin, luseogliflozin or tofogliflozin;inhibitors of protein tyrosine-phosphatase (e.g. trodusquemine);inhibitors of glucose-6-phosphatase; fructose-1,6-bisphosphatasemodulators; glycogen phosphorylase modulators; glucagon receptorantagonists; phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors;pyruvate dehydrogenasekinase (PDK) inhibitors; inhibitors oftyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf.EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, andWO 2006/041976) or of serine/threonine kinases; glucokinase/regulatoryprotein modulators incl. glucokinase activators; glycogen synthasekinase inhibitors; inhibitors of the SH2-domain-containing inositol5-phosphatase type 2 (SHIP2); IKK inhibitors such as high-dosesalicylate; JNK1 inhibitors; protein kinase C-theta inhibitors; beta 3agonists such as ritobegron, YM 178, solabegron, talibegron, N-5984,GRC-1087, rafabegron, FMP825; aldosereductase inhibitors such as AS3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809,and CT-112; SGLT-1 or SGLT-2 inhibitors; KV 1.3 channel inhibitors;GPR40 modulators such as e.g.[(35)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]aceticacid; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists(bromocriptine mesylate [Cycloset]);4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutanoic acid; sirtuinstimulants; and other DPP IV inhibitors.

Metformin is usually given in doses varying from about 500 mg to 2000 mgup to 2500 mg per day using various dosing regimens from about 100 mg to500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mgonce or twice a day, or delayed-release metformin in doses of about 100mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day orabout 500 mg to 2000 mg once a day. Particular dosage strengths may be250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.

For children 10 to 16 years of age, the recommended starting dose ofmetformin is 500 mg given once daily. If this dose fails to produceadequate results, the dose may be increased to 500 mg twice daily.Further increases may be made in increments of 500 mg weekly to amaximum daily dose of 2000 mg, given in divided doses (e.g. 2 or 3divided doses). Metformin may be administered with food to decreasenausea.

A dosage of pioglitazone is usually of about 1-10 mg, 15 mg, 30 mg, or45 mg once a day.

Rosiglitazone is usually given in doses from 4 to 8 mg once (or dividedtwice) a day (typical dosage strengths are 2, 4 and 8 mg).

Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mgonce (or divided twice) a day (typical dosage strengths are 1.25, 2.5and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mgonce (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5and 6 mg).

Glipizide is usually given in doses from 2.5 to 10-20 mg once (or up to40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg),or extended-release glibenclamide in doses from 5 to 10 mg (up to 20 mg)once a day (typical dosage strengths are 2.5, 5 and 10 mg).

Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) oncea day (typical dosage strengths are 1, 2 and 4 mg).

A dual combination of glibenclamide/metformin is usually given in dosesfrom 1.25/250 once daily to 10/1000 mg twice daily. (typical dosagestrengths are 1.25/250, 2.5/500 and 5/500 mg).

A dual combination of glipizide/metformin is usually given in doses from2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250,2.5/500 and 5/500 mg).

A dual combination of glimepiride/metformin is usually given in dosesfrom 1/250 to 4/1000 mg twice daily.

A dual combination of rosiglitazone/glimepiride is usually given indoses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosagestrengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).

A dual combination of pioglitazone/glimepiride is usually given in dosesfrom 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and45/4 mg).

A dual combination of rosiglitazone/metformin is usually given in dosesfrom 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500,2/500, 4/500, 2/1000 and 4/1000 mg).

A dual combination of pioglitazone/metformin is usually given in dosesfrom 15/500 once or twice daily to 15/850 mg thrice daily (typicaldosage strengths are 15/500 and 15/850 mg).

The non-sulphonylurea insulin secretagogue nateglinide is usually givenin doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosagestrengths are 60 and 120 mg); repaglinide is usually given in doses from0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are0.5, 1 and 2 mg). A dual combination of repaglinide/metformin isavailable in dosage strengths of 1/500 and 2/850 mg.

Acarbose is usually given in doses from 25 to 100 mg with meals.Miglitol is usually given in doses from 25 to 100 mg with meals.

Examples of combination partners that lower the lipid level in the bloodare HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin,lovastatin, fluvastatin, pravastatin, pitavastatin and rosuvastatin;fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil,etofibrate and etofyllinclofibrate; nicotinic acid and the derivativesthereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists suchas e.g.{4-[(R)-2-ethoxy-3-(4-trifluoromethyl-phenoxy)-propylsulfanyl]-2-methyl-phenoxy}-aceticacid; inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such asezetimib; substances that bind to bile acid, such as cholestyramine,colestipol and colesevelam; inhibitors of bile acid transport; HDLmodulating active substances such as D4F, reverse D4F, LXR modulatingactive substances and FXR modulating active substances; CETP inhibitorssuch as torcetrapib, JTT-705 (dalcetrapib) or compound 12 from WO2007/005572 (anacetrapib); LDL receptor modulators; MTP inhibitors (e.g.lomitapide); and ApoB100 antisense RNA.

A dosage of atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mgonce a day.

Examples of combination partners that lower blood pressure arebeta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol andcarvedilol; diuretics such as hydrochlorothiazide, chlortalidon,xipamide, furosemide, piretanide, torasemide, spironolactone,eplerenone, amiloride and triamterene; calcium channel blockers such asamlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine,felodipine, lacidipine, lercanipidine, manidipine, isradipine,nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such asramipril, lisinopril, cilazapril, quinapril, captopril, enalapril,benazepril, perindopril, fosinopril and trandolapril; as well asangiotensin II receptor blockers (ARBs) such as telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan andeprosartan.

A dosage of telmisartan is usually from 20 mg to 320 mg or 40 mg to 160mg per day.

Examples of combination partners which increase the HDL level in theblood are Cholesteryl Ester Transfer Protein (CETP) inhibitors;inhibitors of endothelial lipase; regulators of ABC1; LXRalphaantagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/betaregulators, and substances that increase the expression and/or plasmaconcentration of apolipoprotein A-I.

Examples of combination partners for the treatment of obesity aresibutramine; tetrahydrolipstatin (orlistat); alizyme (cetilistat);dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as theCB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptoragonists; NPY5 as well as NPY2 antagonists (e.g. velneperit); beta3-ARagonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such asAPD 356 (lorcaserin); myostatin inhibitors; Acrp30 and adiponectin;steroyl CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS)inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy3-36; orexin receptor antagonists; and tesofensine; as well as the dualcombinations bupropion/naltrexone, bupropion/zonisamide,topiramate/phentermine and pramlintide/metreleptin.

Examples of combination partners for the treatment of atherosclerosisare phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mgto 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958,U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDLantibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1inhibitors.

Further, the certain DPP-4 inhibitor of this invention may be used incombination with a substrate of DPP-4 (particularly with ananti-inflammatory substrate of DPP-4), which may be other than GLP-1,for the purposes according to the present invention, such substrates ofDPP-4 include, for example—without being limited to, one or more of thefollowing:

Incretins:

Glucagon-like peptide (GLP)-1

Glucose-dependent insulinotropic peptide (GIP)

Neuroactive:

Substance P

Neuropeptide Y (NPY)

Peptide YY

Energy homeostasis:

GLP-2

Prolactin

Pituitary adenylate cyclase activating peptide (PACAP)

Other hormones:

PACAP 27

Human chorionic gonadotrophin alpha chain

Growth hormone releasing factor (GHRF)

Luteinizing hormone alpha chain

Insulin-like growth factor (IGF-1)

CCL8/eotaxin

CCL22/macrophage-derived chemokine

CXCL9/interferon-gamma-induced monokine

Chemokines:

CXCL10/interferon-gamma-induced protein-10

CXCL11/interferon-inducible T cell a chemoattractant

CCL3L1/macrophage inflammatory protein 1alpha isoform

LD78beta

CXCL12/stromal-derived factor 1 alpha and beta

Other:

Enkephalins, gastrin-releasing peptide, vasostatin-1,

peptide histidine methionine, thyrotropin alpha

Further or in addition, the certain DPP-4 inhibitor of this inventionmay be used in combination with one or more active substances which areindicated in the treatment of nephrotic syndrome, such as selected fromcorticosteroids (e.g. prednisone or prednisolone), diuretics, ACEinhibitors, ARBs such as e.g. telmisartan, cyclophosphamide,cyclosporine, and/or anticoagulants.

Moreover, optionally in addition, the certain DPP-4 inhibitor of thisinvention may be used in combination with one or more antiplateletagents, such as e.g. (low-dose) aspirin (acetylsalicylic acid), aselective COX-2 or nonselective COX-1/COX-2 inhibitor, or a ADP receptorinhibitor, such as a thienopyridine (e.g. clopidogrel or prasugrel),elinogrel or ticagrelor, or a thrombin receptor antagonist such asvorapaxar.

Yet moreover, optionally in addition, the certain DPP-4 inhibitor ofthis invention may be used in combination with one or more anticoagulantagents, such as e.g. heparin, warfarin, or a direct thrombin inhibitor(such as e.g. dabigatran), or a Faktor Xa inhibitor (such as e.g.rivaroxaban or apixaban or edoxaban or otamixaban).

Still yet moreover, optionally in addition, the certain DPP-4 inhibitorof this invention may be used in combination with one or more agents forthe treatment of heart failure.

The present invention is not to be limited in scope by the specificembodiments described herein. Various modifications of the invention inaddition to those described herein may become apparent to those skilledin the art from the present disclosure. Such modifications are intendedto fall within the scope of the appended claims.

All patent applications cited herein are hereby incorporated byreference in their entireties.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES Reduction in Loss of Podocytes; Expression of Podocalyxin as aMarker of Podocyte Integrity

The expression of podocalyxin is analyzed by immunohistochemistry usinga podocalyxin specific antibody. Kidney sections from male diabeticdb/db mice (10 weeks old at start and treated for 3 months) in thefollowing groups are analyzed: Diabetic control (n=10), linagliptin 3mg/kg (n=8), enalapril 20 mg/kg (n=10) and heterozygous control mice(n=8).

All of the evaluations of the glomerular staining intensities are donesemiquantitatively by two different experts of kidney pathology blindedfor the slides.

The predefined scoring gradient is 0, 1, 2, and 3. 0 means noexpression, whearas 3 is given when expression is highest. Group meansare compared with a non-parametric test. P values less than 0.05 areconsidered significant.

FIG. 1 shows the expression of podocalyxin as a marker for podocyteintegrity in linagliptin-, enalapril- or vehicle-treated diabetic db/dbmice and in healthy control mice.

This prove of concept study in db/db mice (abstract see below) indicatesthat DPP-4 inhibition might offer an new therapeutic approach for thetreatment of proteinuric diseases associated with podocyte loss. Thisstudy clearly demonstrates that the DPP-4 inhibitor linagliptinsignificantly reduces the loss of podocytes in a blood glucoseindependent manner in db/db mice (FIG. 1). Podocyte loss is determinedby podocalyxin staining. Podocalyxin, a sialoglycoprotein, is thought tobe the major constituent of the glycocalyx of podocytes. It is a memberof the CD34 family of transmembrane sialomucin. It coats the secondaryfoot processes of the podocytes. It is negatively charged and thusfunctions to keep adjacent foot processes separated, thereby keeping theurinary filtration barrier open. This function is further supported byknockout studies in mice which reveal an essential role in podocytemorphogenesis.

Renoprotective Effects of Linagliptin; Protection of Podocytes:

Diabetic nephropathy is the main cause of end-stage renal disease. Thisstudy investigated the effects of linagliptin on diabetic nephropathy insevere insulin-resistant and old db/db mice as a model for diabeticnephropathy. Male diabetic db/db mice (10 weeks) were divided into 3groups and treated for 12 weeks with vehicle (n=10), linagliptin 3mg/kg/day (n=8), or the angiotensin converting enzyme (ACE) inhibitorenalapril 20 mg/kg/day (n=10). Heterozygous db/+ mice treated withvehicle were used as controls (n=8). Levels of glucose, triglycerides,insulin, cystatin C and creatinine were analyzed in serum and urinesamples at baseline and monthly thereafter. Body weight, urinary albuminexcretion and OGTT were monitored periodically.

Renal histology (glomerulosclerosis, tubulointerstitial fibrosis) andexpression of the sialoglycoprotein podocalyxin (a marker of podocyteintegrity in the glomeruli, marker for glomerular damage), glucagon-likepeptide 1 receptor (GLP-1R), alpha-smooth muscle actin and type Icollagen were evaluated at the end of the study.

Results:

At 22 weeks, db/db mice showed significantly (p<0.01) higher levels offasting plasma glucose, insulin, and triglycerides, and increased bodyweight compared with healthy db/+ mice. Linagliptin and enalapril hadlimited effects on fasted or post-prandial glucose levels. However,histology analysis showed that tubulointerstitial fibrosis andglomerular mesangial matrix expansion were reduced almost to controllevels in both treatment groups compared with diabetic vehicle (p<0.05for both). Urinary albumin excretion rates and tubulointerstitialfibrosis were significantly decreased in db/db mice treated withlinagliptin compared with those treated with enalapril (both p<0.05).

Podocalyxin expression in db/db vehicle treated mice was significantlyreduced compared with db/+ controls (1.59±0.2 vs 2.65±0.1; p<0.001).Mice treated with linagliptin and enalapril had significantly higherpodocalyxin expression compared with diabetic mice (2.3±0.2 and 2.4±0.2,respectively; p<0.05 for both).

The expression pattern of α-smooth muscle actin was also determined inkidneys as a marker of mesangial cell damage. Linagliptin treatmentnormalized the expression of α-smooth muscle actin-positivemyofibroblasts in the interstitium and glomeruli of diabetic db/db mice.Similar results were obtained for type I collagen deposition.

Immunohistochemical staining of kidney sections revealed a decrease inGLP-1R expression in the cortical glomeruli of db/db mice (1.67±0.07)compared with healthy control mice (2.15±0.1; P<0.01). Linagliptintreatment significantly increased the expression of GLP-1R in theglomeruli of db/db mice (1.90±0.04; P<0.05) compared to vehicle-treateddiabetic db/db mice.

In conclusion, this study suggests that linagliptin protects podocytesfrom injury and may therefore be efficacious in the treatment,prevention or delay in progression of diabetic nephropathy independentof its effect on glucose homeostasis. Further, this study suggests thatlinagliptin is useful for treating, preventing or delaying progressionof glomerulosclerosis and/or tubulointerstitial fibrosis, or glomerularand/or tubulointerstitial injury. Further, this study suggests thatlinagliptin is useful for renoprotection through inhibition of podocytedamage and myofibroblast transformation (reduction of α-SMA expression).

The renoprotective effect of linagliptin in this model seems to be aseffective as treatment with an ACE inhibitor, the current gold standardfor treatment of diabetic nephropathy.

Linagliptin is as Efficacious as Telmisartan in Preventing Renal DiseaseProgression in a Rat Model of Chronic Kidney Disease (Rats with 5/6Nephrectomy)

DPP-4 inhibitors may have kidney-protective properties independent ofglucose control. We compare the effect of linagliptin (LIN) with anangiotensin II receptor antagonist—currently clinical gold standard—onpreventing renal disease progression in a nondiabetic rat model ofchronic renal failure.

Male Wistar rats are allocated to 4 groups: sham operated; 5/6nephrectomy (5/6 NX); 5/6 NX plus LIN (0.083 mg/kg in chow); 5/6 NX plustelmisartan (TEL; 5 mg/kg/d in drinking water). Study duration is 130days; blood pressure and albumin excretion are assessed repeatedly. Atstudy end, kidneys and plasma biomarkers are analyzed. Interstitialfibrosis increases by 69% in 5/6 NX rats vs SHAM rats (p<0.05), anddecreases by 48% (p<0.05) with LIN and 24% with TEL (p=ns) vsPBO-treated 5/6 NX rats. Glomerular size increases by 28% in PBO-treated5/6 NX rats vs SHAM rats (p<0.01), and decreases by 18% (p<0.001) withLIN but not significantly with TEL vs PBO-treated 5/6 NX rats. Theglomerulosclerosic index is significantly increased in 5/6 NX rats vsSHAM rats. There is a trend towards decreased glomerulosclerosis withLIN and TEL. Analysis of collagen type I and III mRNA and proteinconcentrations confirms histopathologic findings. The urinaryalbumin/creatinine ratio increases 14-fold in 5/6 NX rats vs SHAM rats(p<0.001), and decreases by 66% (p<0.05) with LIN and 92% (p<0.01) withTEL vs PBO-treated 5/6 NX rats. Blood pressure is lowered by TEL (31mmHg; p<0.05) and unaffected by LIN. TIMP-1, calbindin, osteopontin andbeta 2 microglobulin (B2M) are significantly increased in thePBO-treated 5/6 NX rats vs SHAM rats. LIN decreases plasmaconcentrations of TIMP-1, calbindin, osteopontin and B2M vs PBO-treated5/6 NX rats (all p<0.05), whereas TEL significantly decreasesosteopontin and TGF-β expression. In summary, LIN is as effective asTEL, in preventing renal disease progression in a model of chronic andprogressive renal failure (rats with 5/6 nephrectomy). The underlyingmolecular mechanisms appear to be different. Linagliptin may be usefulfor treating, preventing, protecting against, reducing the risk of,slowing the progression of or delaying the onset of such conditions,e.g. (micro- or macro-) albuminuria or proteinuria and/or renal functionimpairment or deterioration of renal filtration rate, such as e.g. in(diabetes or non-diabetes) patients suffering therefrom or being at riskthereof.

Linagliptin for Use in Lowering Albuminuria on Top of RecommendedStandard Treatment for Diabetic Nephropathy:

Despite optimal therapy, people with type 2 diabetes (T2D) remain athigh risk for kidney damage, manifest as albuminuria, and many developprogressive renal failure. Further, despite optimal therapy withinhibitors of the renin-angiotensin-aldosterone systeme (RAAS), patientswith type 2 diabetes mellitus (T2DM) remain at an increased risk ofprogressive renal failure and cardiovascular disease, for which albuminuria has emerged as a predictive biomarker. Linagliptin, a DPP-4inhibitor, has previously shown evidence of albumin lowering on top oftelmisartan in mice. We explored the clinical effect of linagliptin onalbuminuria in T2D patients with early diabetic nephropathy. Fourrandomized, double-blind, 24-week, placebo-controlled trials oflinagliptin (5 mg qd) on no, mono, or dual oral glucose-loweringbackground therapy (such as e.g. linagliptin monotherapy, linagliptinadd-on to metformin or linagliptin add-on to metformin plus asulphonylurea, or linagliptin plus metformin initial combination) haddata available for urinary albumin-to-creatinine ratio (UACR) and werepooled for analysis (n=2472). Participants were included in thisanalysis if they had: i) 30≤UACR≤3000 mg/g creatinine; ii) stabletreatment with ACE/ARBs≥4 weeks prior and during the trial; and iii)eGFR>30 ml/min/1.73 m². The endpoint was the percentage change ingeometric mean UACR. In this analysis, 492 (19.9%) patients met UACR andeGFR thresholds of whom 46% received stable ACE/ARB therapy (linagliptinn=168; placebo n=59). Mean baseline A1C and median UACR were 8.2% vs8.5% and 76 vs 78 mg/g creatinine for the linagliptin and placebogroups, respectively. After 24 weeks, placebo-corrected changes in A1Cand FPG were −0.71% and −26 mg/dl, respectively (both p<0.0001).Linagliptin significantly lowered adjusted UACR by 33% (95% CI 22 to42%; p<0.05) with a between group difference vs placebo of −29% (−3 to−48%; p<0.05). Overall, kidney function and blood pressure wereunchanged although more patients on placebo received newanti-hypertensive drugs (17% vs 11% with linagliptin). Sensitivityanalyses in patients not previously treated with RAS blockade (n=265)found similar results. Linagliptin may have kidney-protective propertiesbeyond glucose-lowering effects. This protective effect may beindependent of race. Linagliptin may be useful for treating or loweringalbuminuria on top of standard of care of angiotensin-converting enzyme(ACE) inhibition or angiotensin II receptor blockade (ARB) in T2DMpatients with early diabetic nephropathy.

Linagliptin for Use in Treatment of Albuminuria in Patients with Type 2Diabetes and Diabetic Nephropathy:

Background and aims: Diabetes mellitus has become the most common singlecause of end-stage renal disease and a high proportion of individualswith type 2 diabetes (T2D) are found to have microalbuminuria and overtnephropathy shortly after the diagnosis of their diabetes. Linagliptin,a DPP-4 inhibitor, has recently demonstrated glycaemic efficacy andsafety in T2D patients at advanced stages of kidney disease. Here theclinical effect of linagliptin on albuminuria in T2D patients with earlydiabetic nephropathy is reported.

Materials and methods: Seven randomised, double-blind,placebo-controlled trials (duration 24-52 weeks) of linagliptin (5 mgq.d.) as monotherapy or add-on to various glucose-lowering backgroundtherapies had data available for urinary albumin-to-creatinine ratio(UACR) and were eligible for this analysis (n=4113). Data after 24 weeksof treatment were generated to allow pooling and two sets weredefined: 1) Diabetic nephropathy in earlier stages of T2D (with andwithout oral glucose-lowering background therapies, such as e.g.linagliptin monotherapy, linagliptin add-on to metformin or linagliptinadd-on to metformin plus a sulphonylurea, or linagliptin plus metformininitial combination): participants from four 24-week pivotal phase IIItrials if they had persistent albuminuria, defined as 30≤UACR≤3000 mg/g(eGFR>30 ml/min/1.73 m²) and stable treatment with anangiotensin-converting enzyme inhibitor (ACEi) or angiotensin IIreceptor blocker (ARB) at baseline (ongoing tretament with ACEi or ARB);2) Diabetic nephropathy in elderly patients (various glucose-loweringbackground therapies including insulin, such as e.g. linagliptinmonotherapy, linagliptin add-on to metformin or linagliptin add-on tometformin plus a sulphonylurea, or linagliptin plus metformin initialcombination, or linagliptin in combination with basal insulin): patientsfrom all seven trials, fulfilling UACR criteria 30≤UACR≤3000 mg/g(eGFR>30 ml/min/1.73 m²) and aged 65 years (with or without ongoingtreatment with ACEi or ARB). The endpoint in both sets was thepercentage change in geometric mean UACR after 24 weeks.

Results: For set #1, 492 out of 2472 patients met UACR criteria of whom46% received stable ACEi/ARB therapy (linagliptin, n=168; placebo,n=59). For set #2, 1331 patients were aged ≥65 years of whom 377 (28%)met UACR criteria (linagliptin, n=232; placebo, n=145). Mean baselineHbA1c and median UACR were 8.3% and 76 mg/g overall for set #1, and 8.1%(overall), 77 mg/g (linagliptin) and 86 mg/g (placebo) for set #2. Inset 1, placebo-corrected changes in HbA1c and fasting plasma glucosewere −0.71% and −1.4 mmol/L (−26 mg/dL), respectively (both P<0.0001).Linagliptin significantly lowered adjusted UACR by 33% (95% CI: 22%,42%; P<0.05) with a between-group difference versus placebo of −29% (95%CI: −3%, −48%; P<0.05). In set 2, linagliptin also significantly loweredadjusted UACR by 30% (95% CI: 13%, 43%; P<0.05) with a trend towards areduction versus placebo of −25% (95% CI: −47%, +6%). In all sevenstudies, blood pressure and renal function were not affected to aclinically meaningful extent by either treatment.

Conclusions: In studies up to 52 weeks, linagliptin lowered albuminuriabeyond what may be expected by its glucose-lowering effects. Changes inalbuminuria were seen more rapidly (e.g. with the overall UACR effectoccuring as early as 12 weeks treatment duration) than would be expectedbased on structural changes. A decrease in albuminuria suggests along-term renal benefit.

Further, linagliptin (5 mg qd) lowers (micro)albuminuria in vulnerablediabetic nephropathy patients (with or without additional standardbackground therapy such as e.g. with an ACEi or ARB) such as who areaged 65 years typically having longer diabetes duration (>5 years),renal impairment (such as mild (60 to <90 eGFR ml/min/1.73 m²) ormoderate (30 to <60 eGFR ml/min/1.73 m²) renal impairment) and/or higherbaseline UACR (such as advanced stages of micro- or macroalbuminuria).

In some instances, the diabetic nephropathy patients amenable to thetherapy of this invention may be on hypertension and/or lipid loweringmedication at baseline, such as e.g. on (ongoing) therapy with an ACEinhibitor, ARB, beta-blocker, Calcium-antagonist or diuretic, orcombination thereof, and/or on (ongoing) therapy with a fibrate, niacinor statin, or combination thereof.

Renal Safety and Outcomes with Linagliptin: Meta-Analysis in 5466Patients with Type 2 Diabetes:

Long-term glycemic control in diabetes is associated with reduced riskof renal microvascular complications. Linagliptin has shownnephroprotective effects in animal models and significantly reducedalbuminuria in type 2 diabetes (T2D) associated nephropathy. As theseeffects were independent of short-term glycemic improvements, it wasspeculated that linagliptin may have nephroprotective effects. The aimof this study was to evaluate renal safety/outcomes with linagliptin inphase 3, randomized, double-blind, placebo-controlled trials (≥12 wks).Predefined events from 13 trials were analyzed using a composite primaryendpoint: new onset of a) micro-(first documented UACR≥30 mg/g) or b)macro-(first documented UACR≥300 mg/g) albuminuria, c) CKD (serumcreatinine increase ≥250 μmol/L), d) worsening of CKD (loss in eGFR>50%vs baseline), e) acute renal failure (ARF, standardized MedDRA query)and f) death (any cause). Of 5466 patients included (mean baselineHbA1c: 8.2% and eGFR: 91.4 ml/min/1.73 m2), 3505 received linagliptin 5mg qd and 1961 placebo; cumulative exposure (person yrs) was 1756 and1057, respectively. Events occurred in 448 (12.8%) patients receivinglinagliptin vs 306 (15.6%) for placebo. The hazard ratio (HR) for thecomposite endpoint for linagliptin vs. placebo was 0.84 (95% CI0.72-0.97, p<0.05) and was not significantly altered by race, but waslower in patients <65 vs >65 yrs (HR: 0.77 vs 1.04). RRs wereconsistently reduced for individual renal endpoints: micro-(−15%) andmacroalbuminuria (−12%), new onset (−56%) or worsening of CKD (−24%),ARF (−7%), and death (−23%). In this large meta-analysis, renal safetyand outcomes were significantly improved in patients with T2D treatedwith linagliptin. These data support a direct nephroprotective effect oflinagliptin. Linagliptin may be useful for preventing, reducing ordelaying the onset or progression of micro- or macro-albuminuria, theonset of chronic kidney disease (CKD), the worsening of CKD, the onsetof acute renal failure and/or of death. Thus, linagliptin may be usefulfor preventing, reducing the risk of or delaying the onset or slowingthe progression of renal morbidity and/or mortality, preferably in T2DMpatients.

In some instances, the (at-risk) patients amenable to the renoprotectionor risk-reduction of this invention (e.g. prevention, reduction or delayof the onset or progression of micro- or macro-albuminuria, the onset ofchronic kidney disease (CKD), the worsening of CKD, the onset of acuterenal failure and/or of death) may have renal/cardiovascular historyand/or medications, such as diabetic nephropathy, macrovascular disease(e.g. coronary artery diasease, periperal artery disease,cerebrovascular disease, hypertension), microvascular disease (e.g.diabetic nephropathy, neuropathy, retinopathy), coronary artery disease,cerebrovascular disease, peripheral artery disease, hypertension,ex-smoker or current smoker, and/or on acetylsalicylic acid,antihypertensive and/or lipid lowering medication, such as e.g. on(ongoing) therapy with acetylsalicylic acid, an ACE inhibitor, ARB,beta-blocker, Calcium-antagonist or diuretic, or combination thereof,and/or on (ongoing) therapy with a fibrate, niacin or statin, orcombination thereof.

What is claimed is:
 1. A method of treating or slowing the progressionof diabetic nephropathy in a human type 2 diabetes patient withinadequate control of albuminuria despite therapy with anangiotensin-converting enzyme (ACE) inhibitor or an angiotensin IIreceptor blocker (ARB), said method comprising administering linagliptinin a daily oral amount of 5 mg in combination with theangiotensin-converting enzyme (ACE) inhibitor or the angiotensin IIreceptor blocker (ARB) to the patient.
 2. The method according to claim1, wherein the patient is further administered with a glucose-loweringbackground therapy.
 3. A method of treating the progression ofalbuminuria in a human type 2 diabetes patient with inadequate controlof albuminuria despite therapy with an angiotensin-converting enzyme(ACE) inhibitor or an angiotensin II receptor blocker (ARB), said methodcomprising administering linagliptin in a daily oral amount of 5 mg incombination with the angiotensin-converting enzyme (ACE) inhibitor orthe angiotensin II receptor blocker (ARB) to the patient.
 4. The methodaccording to claim 3, wherein the patient is further administered aglucose-lowering background therapy.
 5. A method of lowering albuminuriain a human type 2 diabetes patient with inadequate control ofalbuminuria despite therapy with an angiotensin-converting enzyme (ACE)inhibitor or an angiotensin II receptor blocker (ARB), said methodcomprising administering linagliptin in a daily oral amount of 5 mg incombination with the angiotensin-converting enzyme (ACE) inhibitor orthe angiotensin II receptor blocker (ARB) to the patient.
 6. The methodaccording to claim 5, wherein the patient is thither administered with aglucose-lowering background therapy.